A bifunctional agent for protein recruitment and / or degradation.

Abstract

For therapeutic purposes, we provide novel compounds, including bifunctional compounds, for degrading target proteins via the ubiquitin-proteasome pathway. [Solution] The compound is of general formula (A) k -L1 or (A) k It has -LQ. Part A of the compound binds to cereblon. L or L1 is a linker. Part Q is a part that binds to a target protein that is sequestered on an E3 ubiquitin ligase and / or degraded upon interaction with the E3 ubiquitin ligase. Part A is an isoindoline derivative, for example, 3-[1-oxo-5-(quinazoline-4-ylamino)isoindoline-2-yl]piperidine-2,6-dione.

Description

[Technical Field]

[0001] As further described herein, the present invention provides novel compounds comprising bifunctional compounds for degrading target proteins via the ubiquitin-proteasome pathway for therapeutic applications.

[0002] Cross-reference with related applications This application claims the benefits of U.S. Provisional Application No. 62 / 949,028, filed on 17 December 2019, the entire contents of which are incorporated herein by reference. [Background technology]

[0003] Protein degradation is a highly regulated and essential process that maintains cellular homeostasis. The selective identification and removal of damaged, misfolded, or excess proteins occurs via the ubiquitin-proteasome pathway (UPP). UPP is essential for regulating almost all cellular processes.

[0004] The covalent attachment of multiple ubiquitin molecules to terminal lysine residues by E3 ubiquitin ligase is a sign of proteasomal degradation, indicating that proteins are digested into small peptides, which ultimately become constituent amino acids that function as building blocks for new proteins.

[0005] Thalidomide and its analogs have been shown to bind to the ubiquitin ligase cereblon, reorienting its ubiquitination activity (Ito, T. et al., Science, 2010, 327:1345). Cereblon forms part of an E3 ubiquitin ligase complex that interacts with damaged DNA-binding proteins, and forms an E3 ubiquitin ligase complex with Cullin4 and the E2-binding protein ROC1 (known as RBX1), which functions as a substrate receptor for selecting proteins for ubiquitination. Lenalidomide binding to cereblon facilitates its subsequent binding to Icarus and Aeolus, leading to their ubiquitination and degradation by the proteasome (Lu, G. et al., Science, 2014, 343:305-309; Kronke, J. et al., Science, 2014, 343:301-305).

[0006] The object of the present invention is to provide novel compounds that bind to cereblon and their use for the treatment of various diseases and disorders, for example, by regulating proteolysis. [Overview of the initiative] [Problems that the invention aims to solve]

[0007] This invention relates to novel compounds, their uses, and their production. The compounds are of general formula (A) k -L1 or (A) k It has -LQ. Part A of the compound binds to cereblon. L or L1 is a linker. Part Q is a portion that binds to a target protein that is sequestered on an E3 ubiquitin ligase and / or degraded upon interaction with the E3 ubiquitin ligase.

[0008] In one embodiment, the present invention relates to general formula (A) k With respect to compounds having -L1, or their salts, enantiomers, stereoisomers, polymorphs, or N-oxides, in the formula,

[0009] A is a moiety that binds to an E3 ubiquitin ligase and has a structure selected from the group consisting of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, and Formula X;

Chemical

[0010] In one embodiment, L1 is -L b -(L a ) t -H is; in the formula, at each occurrence, L a The binding group is CR. 5 R 6 , C(R 5 R 6 )O, C(R 5 R 6 )C(R 5 R 6 )O, SO2, NR 5 , C(R 5 R 6 )NR 5 SO2NR 5 , SONR 5 CONR 5 , NR 5 CONR 6 , NR 5 SO2NR 6 CO, CR 5 =CR 6 , C≡C, SiR 5 R 6 P(O)R 5 , P(O)OR 5 , NR 5 C(=NCN)NR 6 , NR 5 C (=NCN), and NR 5 C(=CNO2)NR 6Independently selected from the group consisting of, each of these is one or more R allowed by valence. w The base, which can be optionally replaced; H stands for hydrogen. L b The following group is selected: [ka] t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0011] In one embodiment, the present invention relates to general formula (A) k With respect to compounds of -LQ, or their salts, enantiomers, stereoisomers, polymorphs, or N-oxides, in the formula,

[0012] A is a compound that binds to E3 ubiquitin ligase and has a structure selected from the group consisting of formulas I, II, III, IV, V, VI, VII, VIII, IX, and X; [ka] Q is a portion that binds to a target protein, which is sequestered on the E3 ubiquitin ligase and / or degraded upon interaction with the E3 ubiquitin ligase; L is the linker; Each A is covalently bonded to L, which is permitted by its valence; R 1 is aryl, -N(R 5 )-XR 6 , -SO2R 5 , or -O(CH2) m R 5 And any of these allows one or more R by valence. w The base, which can be optionally replaced; R 2 is aryl, -NH-(C3-C 10 ) heteroaryl, or -N(R 5)-(CH2) m -X-(CH2) n -R 6 And any of these allows one or more R by valence. w The base, which can be optionally replaced; R 3 This is cyano, aryl, -NH-(C3-C 10 ) Heteroaryl, (C3-C 10 ) Heterocyclo, or -N(R 5 )-(CH2) m -X-(CH2) n -R 6 And any of these allows one or more R by valence. w The base, which can be optionally replaced; R 4 These are halo, cyano, aryl, OR 5 , or -N(R 5 )-(CH2) m -X-(CH2) n -R 6 And any of these allows one or more R by valence. w The base, which can be optionally replaced; R 5 Each instance independently produces H, (C1-C3) alkyl, and (C3-C 10 ) Heterocyclo, (C3-C 10 )Cycloalkyl, -(CH2) n -(C3-C 10 )Cycloalkyl, -(CH2) n -(C3-C 10 ) Heterocyclo, -(CH2) n -Aryl, -(CH2) n -A heteroaryl, aryl, or heteroaryl, each of which contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R 6 Each instance independently produces OH, (C1-C3)alkyl, -(C1-C3)alkoxy, and (C3-C 10 )heterocyclo, (C3-C10)cycloalkyl, -(CH2)n-(C3-C 10)Cycloalkyl, -(CH2)n-(C3-C 10 )heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 are attached together with atoms and nitrogen-containing (C3-C 10 ) form a heterocycle, and each of these contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R 7 is H, (C1-C3) alkyl, or R 7 and R 26 It combines with the carbon atom it is bonded to to form a carbon-carbon double bond; R 8 , R 9 , R 10 , R 11 Each of these is independently H, halo, OH, cyano, (C1-C3)alkyl, (C1-C3)alkoxy, aryl, or heteroaryl, and each of these is one or more R allowed by valence. w The base, which can be optionally replaced; R 12 , R 13 , R 14 , R 15 These are H, NH2, (C1-C3) alkyl, and -N(R) respectively, independently. 5 )-(CH2)mN(R 5 )-XR 6 And, however, R 12 , R 13 , R 14 , and R 15 Three or fewer substituents are H, and each of them has one or more R atoms allowed by valence. w It can be arbitrarily substituted in the base; R 16 is NH2, or -N(R 5 )-(CH2) m -X-(CH2) n -R 6 And any of these allows one or more R by valence. w The base, which can be optionally replaced; R 17is cyano, heteroaryl, -(CH2) m -C(O)OR 6 , or -N(R 5 )-(CH2) m -X-(CH2) n -R 6 And any of these allows one or more R by valence. w The base, which can be optionally replaced; R 18 , R 19 , R 20 , R 21 Each of these is independently H, halo, (C1-C3)alkyl, (C1-C3)alkoxy, or -N(R) 5 )-XR 6 And, however, R 18 , R 19 , R 20 , R 21 Two or fewer substituents among them are H; or R 18 , R 19 They combine with the carbon to which they are attached, (C3-C 10 )Cycloalkyl or (C3-C 10 ) form a heterocycloid, or R 19 , R 20 They combine with the carbon to which they are attached, (C3-C 10 )Cycloalkyl or (C3-C 10 ) form a heterocycloid, or R 20 , R 21 They combine with the carbon to which they are attached, (C3-C 10 )Cycloalkyl or (C3-C 10 ) form heterocycloids, and each of these is allowed by one or more R atoms depending on their valence. w The base, which can be optionally replaced; R 25 These are aryl, heteroaryl, or (C3-C 10 ) are heterocycloidal, and each of these allows one or more R by valence w The base, which can be optionally replaced; R wEach instance independently consists of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkyl, while alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are halo, cyano, oxo (C3-C 10 ) Heterocyclo, (C3-C 10 )Cycloalkyl, -(CH2) n -(C3-C 10 )Cycloalkyl, -(CH2) n -(C3-C 10 ) Heterocyclo, -(CH2) n -Aryl, -(CH2) n -It can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls; X is a bonding group, -SO2-, -(CH2) n C(O)(CH2) m -, -C(O)NH-, -C(O)N(R) w )-, -NHC(O)NH-, or -(CH2) n -and; Y1 is -NHR 25 ,-NHC(O)R 25 , or -CHR 25 R 26 and; m is 0, 1, 2, 3, or 4; k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n is 0, 1, 2, 3, or 4.

[0013] In one embodiment, L is -L b -(L a ) t - is; in the formula, in each instance, La is a bonding group, CR 5 R 6 , C(R5 R 6 )O, C(R 5 R 6 )C(R 5 R 6 )O, SO2, NR 5 , C(R 5 R 6 )NR 5 SO2NR 5 , SONR 5 CONR 5 , NR 5 CONR 6 , NR 5 SO2NR 6 CO, CR 5 =CR 6 , C≡C, SiR 5 R 6 P(O)R 5 , P(O)OR 5 , NR 5 C(=NCN)NR 6 , NR 5 C (=NCN), and NR 5 C(=CNO2)NR 6 Independently selected from the group consisting of, each of these is one or more R allowed by valence. w The base, which can be optionally replaced; L b The following group is selected: [ka] t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0014] In one embodiment, L is -(CH2CH2)t-, -(CH2O)t-, or -(CH2CH2O)t-.

[0015] In one embodiment, part A is selected from the following group: 3-[1-oxo-5-(quinazoline-4-ylamino)isoindoline-2-yl]piperidine-2,6-dione; 3-[5-[(4-aminothieno[2,3-d]pyrimidine-2-yl)amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; N-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindorin-5-yl]acetamide; 3-[5-[(2-aminopyrimidine-4-yl)amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 6-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindoline-5-yl]amino]pyridazine-3-carbonitrile; 3-[[2-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindoline-5-yl]aminoacetyl]aminobenzamide; 2-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindorin-5-yl]aminoacetic acid; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]quinoline-2-carboxamide; 3-[6-[[2-(2-methyl-1-piperidyl)-2-oxo-ethyl]amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 3-[6-[(2-isoindoline-2-yl-2-oxo-ethyl)amino]-1-oxo-isoindoline-2-yl]piperidine-2,6-dione; N-(cyclopropylmethyl)-2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]amino]-N-methylacetamide; Acetic acid; 3-[1-oxo-6-(quinazoline-4-ylamino)isoindoline-2-yl]piperidine-2,6-dione; 3-[6-[[2-(3-methyl-1-piperidyl)-2-oxo-ethyl]amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 3-[6-[(4-methyl-3-oxopyrazine-2-yl)amino]-1-oxoisoindorin-2-yl]piperidine-2,6-dione; 3-[1-oxo-6-(quinoxaline-2-ylamino)isoindoline-2-yl]piperidine-2,6-dione; 3-[6-[(1-methylpyrazolo[3,4-d]pyrimidine-4-yl)amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 3-[6-(5,7-dihydrofl[3,4-d]pyrimidine-2-ylamino)-1-oxoisoindorin-2-yl]piperidine-2,6-dione; 3-[6-[(6-methylpyrimidine-4-yl)amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]amino]-N-phenyl-acetamide; 3-[6-[[2-(2,4-dimethylpiperazine-1-yl)-2-oxo-ethyl]amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 3-[6-(dimethylamino)-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 3-(1-oxo-6-phenyl-isoindoline-2-yl)piperidine-2,6-dione; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]amino]-N,N-dimethylacetamide; 3-[6-[[2-(2-methylmorpholine-4-yl)-2-oxo-ethyl]amino]-1-oxo-isoindoline-2-yl]piperidine-2,6-dione; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]amino]-N-methyl-N-[(1-methylpyrazole-4-yl)methyl]acetamide; N-benzyl-2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]aminoacetamide; 6-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]amino]pyridazine-3-carbonitrile; 3-[6-[(6-methylpyrrolo[3,2-d]pyrimidine-4-yl)amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 2-(dimethylamino)-N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]acetamide; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]-5H-pyrrolo[2,3-b]pyridine-4-carboxamide; N-Cyclopropyl-2-[[2-(2,6-Dioxo-3-Piperidyl)-3-Oxo-Isoindorin-5-yl]aminoacetamide; 3-[1-oxo-6-(2-oxoimidazolidine-1-yl)isoindorin-2-yl]piperidine-2,6-dione; 2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorine-5-carbonitrile; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]amino]propanoic acid; 2-Acetamide-N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]acetamide; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]aminoacetamide; 3-[6-[[2-(3-methyl-5-oxopiperazine-1-yl)-2-oxo-ethyl]amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]acetamide; 3-[6-[[2-(4-methyl-3-oxopiperazine-1-yl)-2-oxo-ethyl]amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]-3H-imidazo[4,5-b]pyridine-6-carboxamide; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]amino]-N-tetrahydropyran-4-yl-acetamide; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]aminoacetic acid; 3-[1-oxo-6-[[2-oxo-2-(1-piperidyl)ethyl]amino]isoindorin-2-yl]piperidine-2,6-dione; 3-(1-oxo-7-phenyl-isoindoline-2-yl)piperidine-2,6-dione; 2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorine-4-carbonitrine; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-4-yl]aminoacetic acid; 3-(7-fluoro-1-oxo-isoindorin-2-yl)piperidine-2,6-dione; 3-(5-amino-1-oxo-3,4-dihydroisoquinoline-2-yl)piperidine-2,6-dione; t-butyl 2-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-1-yl]acetate; 3-[1-(2H-indole-3-yl)-3-oxo-isoindorin-2-yl]piperidine-2,6-dione; 2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-1-carbonitrile; 3-[1-(dimethylamino)-3-oxo-isoindorin-2-yl]piperidine-2,6-dione; 3-(2-oxopyrrolidine-1-yl)piperidine-2,6-dione; 3-(Quinazoline-2-ylamino)piperidine-2,6-dione; (3Z)-3-benzylidenepiperidine-2,6-dione; 3-(Quinoxaline-2-ylamino)piperidine-2,6-dione; 3-(pyrimidine-2-ylamino)piperidine-2,6-dione; N-(2,6-dioxo-3-piperidyl)-2-oxo-3H-pyridine-6-carboxamide; 3-(4-methyl-1,1,3-trioxo-1,2-benzothiazole-2-yl)piperidine-2,6-dione; 3-(8-amino-4-oxo-1,2,3-benzotriazin-3-yl)piperidine-2,6-dione; 3-(5-amino-4-oxo-1,2,3-benzotriazin-3-yl)piperidine-2,6-dione; 3-(4-oxo-1,2,3-benzotriazin-3-yl)piperidine-2,6-dione; 3-(5-methyl-4-oxo-1,2,3-benzotriazin-3-yl)piperidine-2,6-dione; 3-(6-methyl-4-oxo-1,2,3-benzotriazin-3-yl)piperidine-2,6-dione; and 3-(8-methyl-4-oxo-1,2,3-benzotriazin-3-yl)piperidine-2,6-dione.

[0016] In one embodiment, Q is a portion that binds to the target protein, and the target protein is B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, Bcl, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDEI, PDEII, PDEIII, squalene-hopencyclase, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein, Gq, histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosome, glycogen phosphorylase, carbonate anhydrase, chemokine receptor, JAW / STAT, retinoid X receptor, HIV1 protease, HIV1 integrase, influenza, neuramimidase, hepatitis B reverse transcriptase, sodium channel, protein P-glycoprotein (and MRP), tyrosine kinase, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alpha, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, neukinin and receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, Ras / Raf / ME / ERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, c-Kit, TGFβ-activated kinase 1, mammalian rapamycin target, SHP2, androgen receptor, oxytocin receptor, microsome transfer protein inhibitor, 5-alpha reductase, angiotensin II, glycine receptor, noradrenaline reuptake receptor, estrogen receptor, estrogen-related receptor, localized adhesion kinase, Src, endothelin receptor, neuropeptide Y and receptor, adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase, TrkA The group is selected from the following: NGF receptor, beta-amyloid, tyrosine kinase Flk-1, vitronectin receptor, integrin receptor, Her-2 / neu, telomerase, cytosolic phospholipase A2 and EGF receptor tyrosine kinase, ecdysone 20-monooxygenase, ion channels of GABA-gate chloride channels, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium channel protein and chloride channel protein, acetyl-CoA carboxylase, adenyl succinate synthetase, protoporphyrinogen oxidase and enolpyruvir schimate-phosphate synthase.

[0017] In one embodiment, Q is a portion of an Hsp90 inhibitor, kinase inhibitor, phosphatase inhibitor, HDM2 / MDM2 inhibitor, human BET bromodomain inhibitor, HDAC inhibitor, human lysine methyltransferase inhibitor, RAF receptor inhibitor, FKBP inhibitor, angiogenesis inhibitor, aryl hydrocarbon receptor inhibitor, androgen receptor inhibitor, estrogen receptor inhibitor, thyroid hormone receptor inhibitor, HIV protease inhibitor, HIV integrase inhibitor, acyl protein thioesterase 1 inhibitor, or acyl protein thioesterase 2 inhibitor.

[0018] In one embodiment, Q is a portion of a TANK-binding kinase 1 (TBK1) inhibitor, estrogen receptor α (ERα) inhibitor, bromodomain-containing protein 4 (BRD4) inhibitor, androgen receptor (AR) inhibitor, platelet-derived growth factor receptor inhibitor, p38 MAPK inhibitor, Bcr-Abl tyrosine kinase inhibitor, Her2 inhibitor, EGFR inhibitor, MDM2 inhibitor, bromodomain-containing protein 2 (BRD2) inhibitor, HDAC inhibitor, DHFR inhibitor, or c-Myc inhibitor.

[0019] In one embodiment, Q is a portion selected from the group consisting of trimethoprim, vorinostat, tamoxifen, JQ1, nutrin 3, afatinib, chloroalkane, dasatinib, BIRB796, FK-506, simvastatin, rapamycin, and sorafenib.

[0020] In one embodiment, the present invention relates to formula (A) k -LQ or (A) k The present invention relates to a pharmaceutical composition comprising a compound of -L1 and pharmaceutically acceptable carriers, additives, and / or excipients.

[0021] In embodiments, the composition is a bivalent inducer of proteolysis (also known as a proteolysis target chimera (PROTAC)). In embodiments, the composition is a clickable proteolysis-inducing chimera (CLIPTAC). Such a CLIPTAC comprises, in embodiments, (a) a first portion containing a ligand for the target protein; (b) a second portion containing a ligand for an E3 ubiquitin ligase; and (c) a linker portion covalently linking the first and second portions, the linker comprising a covalent bond produced by a bio-orthogonal click reaction between compatible pairs of reactive portions. In embodiments, the composition is an intracellular click-forming proteolysis target chimera (CLIPTAC).

[0022] In one embodiment, the present invention relates to a method for treating a disease in a subject, the method being formula (A) k -LQ or (A) k This involves administering an effective amount of the compound having -L1.

[0023] In one embodiment, the present invention relates to a method for treating a disease in which dysregulated protein activity is the cause of the disease, wherein the method is based on formula (A) k -LQ or (A) k This involves administering an effective amount of the compound having -L1.

[0024] In one embodiment, cancer includes squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, uterine cancer, leukemia, lymphoma, Burkitt lymphoma, non-Hodgkin lymphoma, melanoma, myeloproliferative disorders, multiple myeloma, sarcoma, for example, Ewing's sarcoma. The group is selected from angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, schwannoma, testicular tumor, thyroid cancer, astrocytoma, Hodgkin's disease, Wilms' tumor, and teratoma.

[0025] In another embodiment, the present invention relates to a method for treating or preventing one or more autoimmune diseases or disorders, comprising administering a composition comprising a pharmaceutically effective amount of the compound described herein and a pharmaceutically acceptable carrier to a subject requiring it. In one embodiment, the autoimmune disease or disorder is selected from multiple sclerosis, diabetes mellitus, lupus, celiac disease, Crohn's disease, ulcerative colitis, Guillain-Barré syndrome, scleroderma, Goodpasture syndrome, Wegener's granulomatosis, autoimmune epilepsy, Rasmussen's encephalitis, primary cholangiosclerosis, sclerosing cholangitis, autoimmune hepatitis, Addison's disease, Hashimoto's thyroiditis, fibromyalgia, Meniere's syndrome; transplant rejection (e.g., prevention of allograft rejection); pernicious anemia; rheumatoid arthritis; systemic lupus erythematosus; dermatomyositis; Sjögren's syndrome; lupus erythematosus; multiple sclerosis; myasthenia gravis; Reiter's syndrome; Graves' disease; and other autoimmune diseases or disorders.

[0026] In one embodiment, the subject is a human being.

[0027] The above summary, as well as the following detailed description of the present invention, will be better understood when read in conjunction with the accompanying drawings. [Brief explanation of the drawing]

[0028] [Figure 1] This figure shows the HCl NMR spectrum of intermediate compound 53 in Example 5. [Figure 2] This figure shows LCMS data for trimethoprim-lenalidomide (TMP-LEN). [Figure 3]This figure shows the TMP-LEN hybrid ligand-inducible binding between CRBN and DHFR detected in a MAPPIT-like assay. Recruitment of DHFR to the CRBN bait was induced in the MAPPIT assay using a hybrid molecule consisting of DHFR ligand trimethoprim (TMP) fused to CRBN ligand lenalidomide via a PEG linker. As shown, dose-dependent signaling of TMP-LEN can be observed when CRBN is expressed as a gp130 fusion and DHFR is linked to the MAPPIT chimeric membrane receptor.

[0029] Detailed description of the invention The following is a detailed description of the present invention. Those skilled in the art may modify and adapt the embodiments described herein without departing from the spirit or scope of this disclosure. All publications, patent applications, patents, and other references referenced herein are expressly incorporated in their entirety. What is currently described are novel compounds such as bifunctional compounds, compositions, and methods related to the surprising and unexpected discovery that E3 ubiquitin ligase proteins, e.g., cereblon, ubiquitinate target proteins when the E3 ubiquitin ligase protein and target protein are positioned in close proximity, through bifunctional or chimeric constructs that bind the E3 ubiquitin ligase protein and target protein. Therefore, the present invention relates to the general formula (A) k We provide such compounds having -L1 or (A)kLQ, where A is a portion that binds to an E3 ubiquitin ligase protein; L or L1 is a linker; and Q is a portion that binds to a target protein.

[0030] In one embodiment, the compounds disclosed herein, their pharmaceutically acceptable salts, or their pharmaceutically acceptable compositions may be used to treat disorders mediated by one or more of cereblon, IKZF1, SALL4, and ASS1, such as various cancers and autoimmune diseases or disorders.

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the present invention belongs. The terms used in this description are for the purpose of describing specific embodiments only and are not intended to limit the present invention.

[0032] Where a range of values ​​is provided, unless otherwise explicitly stated in the context (such as in the case of a group containing a number of carbon atoms where the number of carbon atoms for each within that range is provided), it is understood that the upper and lower limits of that range, and any other specified or intervening values ​​within that stated range, up to one-tenth of the lower limit, are included in the present invention. The upper and lower limits of these smaller ranges may independently be included in smaller ranges, but are included in the present invention subject to any particularly excluded limitations in the stated range. Where a stated range includes one or both of the limitations, the range excluding both of those included limitations is also included in the present invention.

[0033] The following terms are used to describe the present invention. If a term is not specifically defined herein, it shall be given the meaning that is technically recognized by those skilled in the art in relation to its use in describing the present invention.

[0034] definition As used herein and in the appended claims, the articles “a” and “an” are used herein to refer to one or more (i.e., at least one) grammatical objects of the article, unless the context clearly indicates otherwise. For example, “element” means one or more elements.

[0035] [ka] This indicates a double bond with an E or Z configuration.

[0036] The term "H" refers to a single hydrogen atom. This radical can, for example, attach to an oxygen atom to form a hydroxyl radical.

[0037] When the term "alkyl" is used alone or within other terms such as "haloalkyl" or "alkylamino," it encompasses linear or branched radicals having 1 to about 12 carbon atoms. More preferred alkyl radicals are "lower alkyl" radicals having 1 to about 6 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, and hexyl. Even more preferred are lower alkyl radicals having 1 or 2 carbon atoms. The terms "alkylenyl" or "alkylene" encompass cross-linked divalent alkyl radicals such as methyleneyl or ethyleneyl. 2 The term “lower alkyl substituted with” does not include the acetal moiety. The term “alkyl” further includes alkyl radicals in which one or more carbon atoms in the chain are substituted with heteroatoms selected from oxygen, nitrogen, or sulfur.

[0038] The term "alkenyl" encompasses linear or branched radicals having at least one carbon-carbon double bond between 2 and about 12 carbon atoms. More preferred alkenyl radicals are "lower alkenyl" radicals having 2 to about 6 carbon atoms. The most preferred lower alkenyl radicals are radicals having 2 to about 4 carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The terms "alkenyl" and "lower alkenyl" encompass radicals having "cis" and "trans" orientations, or "E" and "Z" orientations.

[0039] The term "alkynyl" refers to a linear or branched radical having at least one carbon-carbon triple bond and containing 2 to approximately 12 carbon atoms. More preferred alkynyl radicals are "lower alkynyl" radicals containing 2 to approximately 6 carbon atoms. Most preferred are lower alkynyl radicals containing 2 to approximately 4 carbon atoms. Examples of such radicals include propargyl and butynyl.

[0040] Alkyl, alkylenyl, alkenyl, and alkynyl radicals may optionally be substituted with one or more functional groups such as halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, and heterocyclo.

[0041] The term "halo" refers to halogens such as fluorine, chlorine, bromine, or iodine atoms.

[0042] The term "haloalkyl" encompasses radicals in which one or more alkyl carbon atoms are substituted with a halo as defined above. Specifically, it includes polyhaloalkyl radicals, including monohaloalkyl, dihaloalkyl, and perfluorohaloalkyl. For example, a monohaloalkyl radical may have one of the following atoms within the radical: iodo, bromo, chloro, or fluoro. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or combinations of different halo radicals. "Lower haloalkyl" encompasses radicals having 1 to 6 carbon atoms. More preferably are lower haloalkyl radicals having 1 to 3 carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl.

[0043] The term "perfluoroalkyl" refers to an alkyl radical in which all hydrogen atoms are replaced by fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl.

[0044] The term "hydroxyalkyl" encompasses linear or branched alkyl radicals having 1 to about 10 carbon atoms, any of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having 1 to 6 carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, and hydroxyhexyl. Even more preferred are lower hydroxyalkyl radicals having 1 to 3 carbon atoms.

[0045] The term "alkoxy" encompasses linear or branched oxy-containing radicals, each having an alkyl moiety of 1 to approximately 10 carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicals having 1 to 6 carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy, and tert-butoxy. Even more preferred are lower alkoxy radicals having 1 to 3 carbon atoms. Alkoxy radicals can be further substituted with one or more halo atoms, such as fluoro, chloro, or bromo, to provide "haloalkoxy" radicals. Even more preferred are low haloalkoxy radicals having 1 to 3 carbon atoms. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, and fluoropropoxy.

[0046] The term "aryl," alone or in combination, refers to a carbocyclic aromatic system containing one or two rings, such rings which can be attached together in a fusion manner. The term "aryl" encompasses aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. A more preferred aryl is phenyl. The "aryl" group may have one or more substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, and lower alkylamino. Phenyl substituted with -O-CH2-O- forms an arylbenzodioxolyl substituent.

[0047] The term “heterocyclyl” (or “heterocyclo”) encompasses saturated, partially saturated, and unsaturated heteroatom-containing ring radicals, where the heteroatom may be selected from nitrogen, sulfur, and oxygen. It does not include rings containing -OO-, -OS-, or -SS- moieties. A “heterocyclyl” group may have 1 to 4 substituents, such as hydroxyl, Boc, halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy, amino, and lower alkylamino.

[0048] Examples of saturated heterocyclic radicals include saturated 3-6 member heteromonocyclic groups containing 1-4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolidinyl, piperazinyl]; saturated 3-6 member heteromonocyclic groups containing 1-2 oxygen atoms and 1-3 nitrogen atoms [e.g., morpholinyl]; and saturated 3-6 member heteromonocyclic groups containing 1-2 sulfur atoms and 1-3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocyclyl radicals include dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl.

[0049] Examples of unsaturated heterocyclic radicals, also called "heteroaryl" radicals, include 5-6 member unsaturated heteromonocyclic groups containing 1-4 nitrogen atoms, e.g., pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridadinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; 5-6 member unsaturated heteromonocyclic groups containing an oxygen atom, e.g., pyranyl, 2-furyl, 3-furyl, etc.; and 5-6 member unsaturated heterocyclic groups containing a sulfur atom. Examples include telo-monocyclic groups such as 2-thienyl and 3-thienyl; 5-6 member unsaturated hetero-monocyclic groups containing 1-2 oxygen atoms and 1-3 nitrogen atoms, e.g., oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; and 5-6 member unsaturated hetero-monocyclic groups containing 1-2 sulfur atoms and 1-3 nitrogen atoms, e.g., thiazolyl and thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

[0050] The term heterocyclyl (or heterocyclo) also includes radicals in which a heterocyclic radical fuses / condenses with an aryl radical: an unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, e.g., indolyl, isoindolyl, indolidinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo[1,5-b]pyridazinyl]; and 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms. Unsaturated condensed heterocyclic groups containing atoms [e.g., benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic groups containing 1-2 sulfur atoms and 1-3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl]; saturated, partially unsaturated, and unsaturated condensed heterocyclic groups containing 1-2 oxygen or sulfur atoms [e.g., benzofuryl, benzothienyl, 2,3-dihydro-benzo[1,4]dioxynyl, and dihydrobenzofuryl]. Preferred heterocyclic radicals include 5-10 membered condensed or uncondensed radicals. More preferred examples of heteroaryl radicals include quinolyl, isoquinolyl, imidazolyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl, and pyrazinyl. Other preferred heteroaryl radicals are 5-membered or 6-membered heteroaryls selected from sulfur, nitrogen, and oxygen, and containing one or two heteroatoms selected from thienyl, furyl, pyrrolyl, indazolyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyl, and pyrazinyl.

[0051] Specific examples of non-nitrogen-containing heteroaryls include pyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzofuryl, and benzothienyl.

[0052] Specific examples of partially saturated and saturated heterocyclyls include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanil, chromanil, 1,2-dihydroquinolyl, and 1,2,3,4-tetrahydro-iso Examples include quinolyl, 1,2,3,4-tetrahydroquinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-azafluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ'-benzo[d]isothiazolyl-6-yl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl.

[0053] Therefore, the term "heterocycloidal" encompasses the following ring systems. [ka] For example, TIFF2026143564000008.tif201162.

[0054] The term "sulfonyl," whether used alone or in conjunction with other terms such as alkylsulfonyl, refers to the divalent radical -SO2-.

[0055] The terms "sulfamyl," "aminosulfonyl," and "sulfonamidyl" refer to sulfonyl radicals that are substituted with amine radicals to form sulfonamides (-SO2NH2).

[0056] The term "alkylaminosulfonyl" includes "N-alkylaminosulfonyl" radicals in which a sulfamyl radical is independently substituted with one or two alkyl radicals. More preferred alkylaminosulfonyl radicals are "lower alkylaminosulfonyl" radicals having 1 to 6 carbon atoms. Even more preferred are lower alkylaminosulfonyl radicals having 1 to 3 carbon atoms. Examples of such lower alkylaminosulfonyl radicals include N-methylaminosulfonyl and N-ethylaminosulfonyl.

[0057] The term "carboxy" or "carboxyl," whether used alone or in conjunction with other terms such as "carboxyalkyl," means -CO2H.

[0058] The term "carbonyl," whether used alone or in conjunction with other terms such as "aminocarbonyl," means -(C=O)-.

[0059] The term "aminocarbonyl" refers to the amide group of the formula C(=O)NH2.

[0060] The terms "N-alkylaminocarbonyl" and "N,N-dialkylaminocarbonyl" refer to aminocarbonyl radicals independently substituted with one or two alkyl radicals, respectively. More preferred is the "lower alkylaminocarbonyl," which has the aforementioned lower alkyl radical attached to the aminocarbonyl radical.

[0061] The terms "N-arylaminocarbonyl" and "N-alkyl-N-arylaminocarbonyl" refer, respectively, to an aryl radical or an aminocarbonyl radical substituted with one alkyl and one aryl radical.

[0062] The terms "heterocyclylalkylenyl" and "heterocyclylalkyl" encompass heterocyclic substituted alkyl radicals. More preferred heterocyclylalkyl radicals are "5-membered or 6-membered heteroarylalkyl" radicals having an alkyl moiety of 1 to 6 carbon atoms and a 5-membered or 6-membered heteroaryl radical. Even more preferred are lower heteroarylalkyl radicals having an alkyl moiety of 1 to 3 carbon atoms. Examples include radicals such as pyridylmethyl and thienylmethyl.

[0063] The term "aralkyl" encompasses aryl-substituted alkyl radicals. Preferred aralkyl radicals are "lower aralkyl" radicals having an aryl radical attached to an alkyl radical having 1 to 6 carbon atoms. Even more preferred are "phenylalkylenyl" radicals attached to an alkyl moiety having 1 to 3 carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, and phenylethyl. The aryl in the aralkyl can be further substituted with halo, alkyl, alkoxy, halcoalkyl, and haloalkoxy.

[0064] The term "alkylthio" encompasses radicals including linear or branched alkyl radicals with 1 to 10 carbon atoms attached to a divalent sulfur atom. More preferably are lower alkylthio radicals having 1 to 3 carbon atoms. An example of "alkylthio" is methylthio(CH3S-).

[0065] The term "haloalkylthio" encompasses radicals containing 1 to 10 carbon atoms attached to a divalent sulfur atom, including haloalkyl radicals. More preferably, lower haloalkylthio radicals have 1 to 3 carbon atoms. An example of a "haloalkylthio" is trifluoromethylthio.

[0066] The term "alkylamino" encompasses "N-alkylamino" and "N,N-dialkylamino," where the amino group is independently substituted with one alkyl radical and two alkyl radicals, respectively. More preferred alkylamino radicals are "lower alkylamino" radicals having one or two alkyl radicals of 1 to 6 carbon atoms attached to the nitrogen atom. Even more preferred are lower alkylamino radicals having 1 to 3 carbon atoms. Preferred alkylamino radicals may be mono- or dialkylaminos such as N-methylamino, N-ethylamino, N,N-dimethylamino, and N,N-diethylamino.

[0067] The term "arylamino" refers to an amino group that is substituted with one or two aryl radicals, such as N-phenylamino. The arylamino radical can be further substituted at the aryl ring portion of the radical.

[0068] The term "heteroarylamino" refers to an amino group that is substituted with one or two heteroaryl radicals, such as N-thienylamino. Heteroarylamino radicals can be further substituted at the heteroaryl ring portion of the radical.

[0069] The term "aralkylamino" refers to an amino group substituted with one or two aralkyl radicals. More preferably, these are phenyl-C1-C3-alkylamino radicals, such as N-benzylamino. The aralkylamino radical can be further substituted at the aryl ring moiety.

[0070] The terms "N-alkyl-N-arylamino" and "N-aralkyl-N-alkylamino" refer to an amino group independently substituted with one aralkyl and one alkyl radical, or one aryl and one alkyl radical, respectively.

[0071] The term "aminoalkyl" encompasses linear or branched alkyl radicals having 1 to about 10 carbon atoms, any of which may be substituted with one or more amino radicals. More preferred aminoalkyl radicals are "lower aminoalkyl" radicals having 1 to 6 carbon atoms and one or more amino radicals. Examples of such radicals include aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl. Even more preferred are lower aminoalkyl radicals having 1 to 3 carbon atoms.

[0072] The term "alkylaminoalkyl" encompasses alkyl radicals substituted with alkylamino radicals. More preferred alkylaminoalkyl radicals are "lower alkylaminoalkyl" radicals having alkyl radicals with 1 to 6 carbon atoms. Even more preferred are lower alkylaminoalkyl radicals having alkyl radicals with 1 to 3 carbon atoms. Preferred alkylaminoalkyl radicals can be mono- or dialkyl substituted, such as N-methylaminomethyl, N,N-dimethylaminoethyl, and N,N-diethylaminomethyl.

[0073] The term "alkylaminoalkyl" encompasses alkoxy radicals substituted with alkylamino radicals. More preferred alkylaminoalkoxy radicals are "lower alkylaminoalkoxy" radicals having 1 to 6 carbon atom alkoxy radicals. Even more preferred are lower alkylaminoalkoxy radicals having 1 to 3 carbon atom alkyl radicals. Preferred alkylaminoalkoxy radicals can be mono- or dialkyl-substituted, such as N-methylaminoethoxy, N,N-dimethylaminoethoxy, and N,N-diethylaminoethoxy.

[0074] The term "alkylaminoalkoxyalkoxy" encompasses alkoxy radicals substituted with alkylaminoalkoxy radicals. More preferred alkylaminoalkoxyalkoxy radicals are "lower alkylaminoalkoxyalkoxy" radicals having 1 to 6 carbon atom alkoxy radicals. Even more preferred are lower alkylaminoalkoxyalkoxy radicals having 1 to 3 carbon atom alkyl radicals. Preferred alkylaminoalkoxyalkoxy radicals may be mono- or dialkyl substituted, such as N-methylaminomethoxyethoxy, N-methylaminoethoxyethoxy, N,N-dimethylaminoethoxyethoxy, and N,N-diethylaminomethoxymethoxy.

[0075] The term "carboxyalkyl" encompasses linear or branched alkyl radicals having 1 to about 10 carbon atoms, one of which may be substituted with one or more carboxyl radicals. More preferred carboxyalkyl radicals are "lower carboxyalkyl" radicals having 1 to 6 carbon atoms and one carboxyl radical. Examples of such radicals include carboxymethyl and carboxypropyl. Even more preferred are lower carboxyalkyl radicals having 1 to 3 CH2 groups.

[0076] The term "halosulfonyl" encompasses sulfonyl radicals substituted with halogen radicals. Examples of such halosulfonyl radicals include chlorosulfonyl and fluorosulfonyl.

[0077] The term "arylthio" encompasses aryl radicals consisting of 6 to 10 carbon atoms attached to a divalent sulfur atom. An example of "arylthio" is phenylthio.

[0078] The term "aralkylthio" encompasses the above-mentioned aralkyl radicals attached to a divalent sulfur atom. More preferably, phenyl-C1-C3-alkylthio radicals are used. An example of "aralkylthio" is benzylthio.

[0079] The term "aryloxy" encompasses aryl radicals, as defined above, that are attached to an oxygen atom and optionally substituted. An example of such a radical is phenoxy.

[0080] The term "aralkoxy" encompasses oxy-containing aralkyl radicals attached to other radicals via an oxygen atom. A more preferred aralkoxy radical is a "lower aralkoxy" radical having an optionally substituted phenyl radical attached to a lower alkoxy radical as described above.

[0081] The term "heteroaryloxy" encompasses heteroaryl radicals, as defined above, that are attached to an oxygen atom and optionally substituted.

[0082] The term "heteroarylalkoxy" encompasses oxy-containing heteroarylalkyl radicals attached to other radicals via an oxygen atom. More preferred heteroarylalkoxy radicals are "lower heteroarylalkoxy" radicals having optionally substituted heteroaryl radicals attached to lower alkoxy radicals as described above.

[0083] The term "cycloalkyl" includes saturated carbocyclic groups. Preferred cycloalkyl groups include C3-C6 rings. More preferred compounds include cyclopentyl, cyclopropyl, and cyclohexyl.

[0084] The term "cycloalkylalkyl" encompasses cycloalkyl-substituted alkyl radicals. Preferred cycloalkylalkyl radicals are "lower cycloalkylalkyl" radicals having a cycloalkyl radical attached to an alkyl radical having 1 to 6 carbon atoms. Even more preferred are "5-6 membered cycloalkylalkyls" attached to an alkyl moiety having 1 to 3 carbon atoms. An example of such a radical is cyclohexylmethyl. The cycloalkyl in the radical can be further substituted with halo, alkyl, alkoxy, and hydroxyl.

[0085] The term "cycloalkenyl" includes carbocyclic groups having one or more carbon-carbon double bonds, such as "cycloalkyldienyl" compounds. Preferred cycloalkenyl groups include C3-C6 rings. More preferred compounds include, for example, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cycloheptadienyl.

[0086] The term "comprising" means that it includes the listed components but excludes other elements, and is open-ended.

[0087] A group or atom that substitutes for a hydrogen atom is also called a substituent.

[0088] A particular molecule or group may have one or more substituents, depending on the number of hydrogen atoms that can be substituted.

[0089] The symbol "-" represents a covalent bond and can be used to indicate an attachment site to another group in a radical group. In chemical structures, the symbol is commonly used to represent a methyl group within a molecule.

[0090] The term "therapeutic dose" means the amount of a compound that improves, reduces or eliminates one or more symptoms of a particular disease or condition, or prevents or delays the onset of one or more symptoms of a particular disease or condition.

[0091] The terms "patient" and "subject" can be used interchangeably and refer to animals such as dogs, cats, cows, horses, sheep, and humans. A specific patient is a mammal. The term "patient" can include both male and female.

[0092] The term "pharmaceutically acceptable" means that a reference substance, such as a compound of formula I, a salt of a compound of formula I, a formulation containing a compound of formula I, or certain excipients, is suitable for administration to a patient.

[0093] Terms such as "to treat," "to treat," or "treatment" include preventative (e.g., prophylactic) and palliative treatments.

[0094] The term "excipients" refers to any pharmaceutically acceptable additives, carriers, diluents, adjuvants, or other components other than the active pharmaceutical ingredient (API), which are typically included in formulations and / or administration to patients.

[0095] The term "cancer" refers to a physiological condition in mammals characterized by unregulated cell growth. Common classes of cancer include carcinomas, lymphomas, sarcomas, and blastomas.

[0096] composition The compounds of the present invention are administered to patients in therapeutically effective doses. The compounds can be administered alone or as part of a pharmaceutically acceptable composition or formulation. Furthermore, the compounds or compositions can be administered, for example, all at once by bolus injection, multiple times, for example, by a series of tablets, or substantially uniformly over a period of time by transdermal delivery. It should also be noted that the dose of the compound may vary over time.

[0097] The compounds of the present invention may be administered to a patient, as needed, orally, rectally, parenterally (e.g., intravenously, intramuscularly, or subcutaneously), intracisional, intravaginally, intraperitoneally, intravesically, topically (e.g., as a powder, ointment, or drop), or as a buccal or nasal spray. All methods used by those skilled in the art for administering the pharmaceutically active agent are intended.

[0098] Compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as propylene glycol, polyethylene glycol, and glycerol), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters, such as ethyl oleate. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0099] These compositions may also contain adjuvants such as preservatives, humectants, emulsifiers, and dispersants. Microbial contamination can be prevented by adding various antimicrobial and antifungal agents such as parabens, chlorobutanol, phenol, and sorbic acid. The inclusion of isotonic agents, such as sugars and sodium chloride, may also be desirable. Long-term absorption of injectable pharmaceutical compositions can be achieved by using absorption-delaying agents, such as aluminum monostearate and gelatin.

[0100] Solid dosage forms for oral administration include capsules, tablets, powders, and granules. In such solid dosage forms, the active compound is composed of at least one inert common excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (a) fillers or bulking agents, e.g., starch, lactose, sucrose, mannitol, and silicic acid; (b) binders, e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, e.g., glycerol; (d) disintegrants, e.g., agar, calcium carbonate, potato or (i) The ingredients are mixed with tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (a) solution retarders, e.g., paraffin; (f) absorption enhancers, e.g., quaternary ammonium compounds; (g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; (h) adsorbents, e.g., kaolin and bentonite; (i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In the case of capsules and tablets, the dosage form may also contain buffers.

[0101] Similar types of solid compositions can also be used as fillers in soft and rigid gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0102] Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be prepared using coatings and shells, such as enteric coatings and others well known in the art. These may also contain opacifying agents, and their composition may be such that they release one or more active compounds in a delayed manner in specific parts of the intestinal tract. Examples of usable embedding compositions are polymers and waxes. The active compounds may also be in microencapsulated form, together with one or more of the above excipients, where appropriate.

[0103] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may include inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan fatty acid esters, or mixtures of these substances.

[0104] In addition to such inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances. The suspension may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, metahydroxyaluminum, bentonite, agar and tragacanth, or mixtures thereof.

[0105] The compositions for rectal administration are preferably suppositories, which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or suppository wax, which are solid at normal room temperature but liquid at body temperature, and thus dissolve in the rectum or vaginal cavity to release the active ingredient.

[0106] Dosage forms for topical administration of the compounds of the present invention include ointments, powders, sprays, and inhalants. The active or compatible compound is mixed under sterile conditions with a physiologically acceptable carrier and any necessary preservatives, buffers, or propellants. Ophthalmic formulations, ophthalmic ointments, powders, and solutions are also intended to be within the scope of the present invention.

[0107] The compounds of the present invention can be administered to patients at dosage levels ranging from approximately 0.1 to approximately 3,000 mg per day. For a normal adult human being weighing approximately 70 kg, a dosage range of approximately 0.01 mg to approximately 100 mg per kilogram of body weight is usually sufficient. The specific dosage and dosage range that can be used depends on many factors, including the patient's requirements, the severity of the condition or disease being treated, and the pharmacological activity of the compound being administered. Determining the dosage range and optimal dosage for a particular patient is within the scope of those skilled in the art.

[0108] The compounds of the present invention can be administered as pharmaceutically acceptable salts, esters, amides, or prodrugs. The term "salt" refers to the inorganic and organic salts of the compounds of the present invention. Salts can be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound in its free base or acid form separately with a suitable organic or inorganic base or acid, and then isolating the salts thus formed. Typical salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate. Salts may include cations based on alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, such as, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. See, for example, SMBerge, et al., "Pharmaceutical Salts", J Pharm Sci, 66:1-19 (1977).

[0109] Examples of pharmaceutically acceptable esters of the compounds of the present invention include C1-C8 alkyl esters. Acceptable esters also include C5-C7 cycloalkyl esters and arylalkyl esters such as benzyl. C1-C4 alkyl esters are commonly used. Esters of the compounds of the present invention can be prepared according to methods well known in the art.

[0110] Examples of pharmaceutically acceptable amides of the compounds of the present invention include amides derived from ammonia, primary C1-C8 alkylamines, and secondary C1-C8 dialkylamines. In the case of secondary amines, the amine may also be in the form of a 5 or 6-membered heterocycloalkyl group containing at least one nitrogen atom. Ammonia-derived amides, C1-C3 primary alkylamines, and C1-C2 dialkyl secondary amines are commonly used. Amides of the compounds of the present invention can be prepared according to methods well known to those skilled in the art.

[0111] The term "prodrug" refers to a compound that is transformed in vivo to produce the compound of the present invention. Transformation can occur through various mechanisms, such as hydrolysis in the blood. Discussions regarding the use of prodrugs are published in T. Higuchi and W. Stella, "Prodrugs as Novel Delivery Systems," Vol. 14, the ACSSymposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0112] For illustrative purposes, if the compound of the present invention contains a carboxylic acid functional group, the prodrug may include an ester formed by substituting a hydrogen atom of the acid group with any of the following groups: (C1-C8 alkyl, (C2-C 12Alkanoyloxymethyl, 1-(alkanoyloxy)ethyl with 4-9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl with 5-10 carbon atoms, alkoxycarbonyloxymethyl with 3-6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl with 4-7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl with 5-8 carbon atoms, N-(alkoxycarbonyl)amino with 3-9 carbon atoms Methyl, 1-(N-(alkoxycarbonyl)aminomethyl) having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C1-C2)alkylamino(C2-C3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di(C1-C2)alkylcarbamoyl-(C1-C2)alkyl, and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl.

[0113] Similarly, if the compounds of the present invention contain an alcohol functional group, the prodrug may be formed by substituting the hydrogen atoms of the alcohol group with any group, such as (C1-C6)alkanoyloxymethyl, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)ethyl, (C1-C6)alkoxycarbonyloxymethyl, N-(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1-C6)alkanoyl, α-amino(C1-C4)alkanoyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently a naturally occurring L-amino acid, -P(O)(OH)2, -P(O)(O(C1-C6)alkyl)2, or glycosyl (a radical resulting from the removal of a hydroxyl group from the hemiacetal form of a carbohydrate).

[0114] The compounds of the present invention may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds, including racemic mixtures, as well as mixtures thereof, are intended to form part of the present invention. Furthermore, the present invention intends all geometric and positional isomers. For example, if the compound contains a double bond, both cis and trans forms (designated S and E, respectively), and mixtures thereof are intended.

[0115] Mixtures of stereoisomers, such as diastereomer mixtures, can be separated into their individual stereochemical components based on their physicochemical differences by known methods such as chromatography and / or fractional crystallization. Enantiomers can also be separated by converting the enantiomer mixture into a diastereomer mixture through reaction with a suitable optically active compound (e.g., an alcohol), separating the diastereomers, and converting the individual diastereomers back into their corresponding pure enantiomers (e.g., by hydrolysis). In addition, some compounds may be atropisomers (e.g., substituted biaryls).

[0116] The compounds of the present invention can exist in both solvated and solvated forms using pharmaceutically acceptable solvents such as water (hydrate) and ethanol. The present invention intends to encompass both solvated and solvated forms.

[0117] The compounds of the present invention may also exist in different tautomer forms. All tautomers of the compounds of the present invention are intended. For example, all tautomer forms of the tetrazole moiety are included in the present invention. Also, for example, all ketoenol or imine enamine forms of the compounds are included in the present invention.

[0118] Those skilled in the art will recognize that the names and structures of the compounds included herein may be based on specific tautomers of the compounds. While only the names or structures of specific tautomers may be used, all tautomers are intended to be included in the present invention unless otherwise specified.

[0119] The present invention is also intended to encompass compounds synthesized in vitro using experimental techniques such as those well known to synthetic chemists, or compounds synthesized using in vivo techniques such as metabolism, fermentation, or digestion. It is also intended that the compounds of the present invention may be synthesized using a combination of in vitro and in vivo techniques.

[0120] The present invention also includes isotope-labeled compounds, which are identical to those described herein, but in which one or more atoms are substituted with atoms having atomic weights or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 16 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl is an example. In one embodiment, the present invention relates to one or more hydrogen atoms that are deuterium ( 2 This concerns compounds in which H atoms are substituted.

[0121] Compounds of the present invention containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Specific isotope-labeled compounds of the present invention, for example, 3 H and 14 The incorporation of radioactive isotopes such as 13C is useful in drug and / or substrate tissue distribution assays. Tritiation, i.e. 3 H, and carbon 14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. Furthermore, heavier isotopes such as deuterium, i.e. 2Substitution with H can result in greater metabolic stability, for example, certain therapeutic benefits arising from an increased in vivo half-life or a reduction in the required dosage, and is therefore preferable in some situations. The isotope-labeled compounds of the present invention can generally be prepared by replacing the non-isotopically labeled reagent with a readily available isotope-labeled reagent.

[0122] The compounds of the present invention can exist in various solid states, including crystalline states, and also in amorphous states. Different crystalline states, also called polymorphs, and polymorphic states of the compounds of the present invention are intended as part of the present invention.

[0123] All patents, published patent applications, and other publications cited herein are incorporated herein by reference.

[0124] compound In one embodiment, the present invention relates to general formula (A) k With respect to compounds having -L1, or their salts, enantiomers, stereoisomers, polymorphs, or N-oxides, in the formula,

[0125] A is a portion that binds to E3 ubiquitin ligase and has a structure selected from the group consisting of formulas I, II, III, IV, V, VI, VII, VIII, IX, and X; [ka] (In the formula, L1 is the linker; Each A is covalently linked to L1, which is permitted by valence; R 1 is aryl, -N(R 5 )-XR 6 , -SO2R 5 , or -O(CH2) m R 5 And any of these allows one or more R by valence. w The base, which can be optionally replaced; R2 is aryl, -NH-(C3-C 10 ) heteroaryl, or -N(R 5 )-(CH2) m -X-(CH2) n -R 6 And any of these allows one or more R by valence. w The base, which can be optionally replaced; R 3 This is cyano, aryl, -NH-(C3-C 10 ) Heteroaryl, (C3-C 10 ) Heterocyclo, or -N(R 5 )-(CH2) m -X-(CH2) n -R 6 And any of these allows one or more R by valence. w The base, which can be optionally replaced; R 4 These are halo, cyano, aryl, OR 5 , or -N(R 5 )-(CH2) m -X-(CH2) n -R 6 And any of these allows one or more R by valence. w The base, which can be optionally replaced; R 5 Each instance independently produces H, (C1-C3) alkyl, and (C3-C 10 ) Heterocyclo, (C3-C 10 )Cycloalkyl, -(CH2) n -(C3-C 10 )Cycloalkyl, -(CH2) n -(C3-C 10 ) Heterocyclo, -(CH2) n -Aryl, -(CH2) n -A heteroaryl, aryl, or heteroaryl, each of which contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R 6Each instance independently produces OH, (C1-C3)alkyl, -(C1-C3)alkoxy, and (C3-C 10 )heterocyclo, (C3-C10)cycloalkyl, -(CH2)n-(C3-C 10 )Cycloalkyl, -(CH2)n-(C3-C 10 )heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 are attached together with atoms and nitrogen-containing (C3-C 10 ) form a heterocycle, and each of these contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R 7 is H, (C1-C3) alkyl, or R 7 and R 26 It combines with the carbon atom it is bonded to to form a carbon-carbon double bond; R 8 , R 9 , R 10 , R 11 Each of these is independently H, halo, OH, cyano, (C1-C3)alkyl, (C1-C3)alkoxy, aryl, or heteroaryl, and each of these is one or more R allowed by valence. w The base, which can be optionally replaced; R 12 , R 13 , R 14 , R 15 These are H, NH2, (C1-C3) alkyl, and -N(R) respectively, independently. 5 )-(CH2)mN(R 5 )-XR 6 And, however, R 12 , R 13 , R 14 , and R 15 Three or fewer substituents are H, and each of them has one or more R atoms allowed by valence. w It can be arbitrarily substituted in the base; R 16 is NH2, or -N(R 5 )-(CH2) m -X-(CH2)n -R 6 And any of these allows one or more R by valence. w The base, which can be optionally replaced; R 17 is cyano, heteroaryl, -(CH2) m -C(O)OR 6 , or -N(R 5 )-(CH2) m -X-(CH2) n -R 6 And any of these allows one or more R by valence. w The base, which can be optionally replaced; R 18 , R 19 , R 20 , R 21 Each of these is independently H, halo, (C1-C3)alkyl, (C1-C3)alkoxy, or -N(R) 5 )-XR 6 And, however, R 18 , R 19 , R 20 , R 21 Two or fewer substituents among them are H; or R 18 , R 19 They combine with the carbon to which they are attached, (C3-C 10 )Cycloalkyl or (C3-C 10 ) form a heterocycloid, or R 19 , R 20 They combine with the carbon to which they are attached, (C3-C 10 )Cycloalkyl or (C3-C 10 ) form a heterocycloid, or R 20 , R 21 They combine with the carbon to which they are attached, (C3-C 10 )Cycloalkyl or (C3-C 10 ) form heterocycloids, and each of these is allowed by one or more R atoms depending on their valence. w The base, which can be optionally replaced; R 25 These are aryl, heteroaryl, or (C3-C10 ) are heterocycloidal, and each of these allows one or more R by valence w The base, which can be optionally replaced; R w Each instance independently consists of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkyl, while alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are halo, cyano, oxo (C3-C 10 ) Heterocyclo, (C3-C 10 )Cycloalkyl, -(CH2) n -(C3-C 10 )Cycloalkyl, -(CH2) n -(C3-C 10 ) Heterocyclo, -(CH2) n -Aryl, -(CH2) n -It can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls; X is a bonding group, -SO2-, -(CH2) n C(O)(CH2) m -, -C(O)NH-, -C(O)N(R) w )-, -NHC(O)NH-, or -(CH2) n -and; Y1 is -NHR 25 ,-NHC(O)R 25 , or -CHR 25 R 26 and; m is 0, 1, 2, 3, or 4; k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n is 0, 1, 2, 3, or 4.

[0126] In one embodiment, L1 is -L b -(L a ) t -H is; in the formula, at each occurrence, L a The binding group is CR. 5 R 6 , C(R 5 R 6 )O, C(R 5 R 6 )C(R 5 R 6 )O, SO2, NR 5 , C(R 5 R 6 )NR 5 SO2NR 5 , SONR 5 CONR 5 , NR 5 CONR 6 , NR 5 SO2NR 6 CO, CR 5 =CR 6 , C≡C, SiR 5 R 6 P(O)R 5 , P(O)OR 5 , NR 5 C(=NCN)NR 6 , NR 5 C (=NCN), and NR 5 C(=CNO2)NR 6 Independently selected from the group consisting of, each of these is one or more R allowed by valence. w The base, which can be optionally replaced; H stands for hydrogen. L b The following group is selected: [ka] In the formula, t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0127] In one embodiment, part A is selected from the compounds listed in Table 6 of Example 6.

[0128] In one embodiment, the present invention relates to general formula (A) k - Relating to compounds of LQ, or their salts, enantiomers, stereoisomers, polymorphs, or N-oxides (wherein the formula,

[0129] A is a compound that binds to E3 ubiquitin ligase and has a structure selected from the group consisting of formulas I, II, III, IV, V, VI, VII, VIII, IX, and X; [ka] Q is a portion that binds to a target protein, which is sequestered on the E3 ubiquitin ligase and / or degraded upon interaction with the E3 ubiquitin ligase; L is the linker; Each A is covalently bonded to L, which is permitted by its valence; R 1 is aryl, -N(R 5 )-XR 6 , -SO2R 5 , or -O(CH2) m R 5 And any of these allows one or more R by valence. w The base, which can be optionally replaced; R 2 is aryl, -NH-(C3-C 10 ) heteroaryl, or -N(R 5 )-(CH2) m -X-(CH2) n -R 6 And any of these allows one or more R by valence. w The base, which can be optionally replaced; R 3 This is cyano, aryl, -NH-(C3-C 10 ) Heteroaryl, (C3-C 10 ) Heterocyclo, or -N(R 5 )-(CH2) m -X-(CH2) n -R 6And any of these allows one or more R by valence. w The base, which can be optionally replaced; R 4 These are halo, cyano, aryl, OR 5 , or -N(R 5 )-(CH2) m -X-(CH2) n -R 6 And any of these allows one or more R by valence. w The base, which can be optionally replaced; R 5 Each instance independently produces H, (C1-C3) alkyl, and (C3-C 10 ) Heterocyclo, (C3-C 10 )Cycloalkyl, -(CH2) n -(C3-C 10 )Cycloalkyl, -(CH2) n -(C3-C 10 ) Heterocyclo, -(CH2) n -Aryl, -(CH2) n -A heteroaryl, aryl, or heteroaryl, each of which contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R 6 Each instance independently produces OH, (C1-C3)alkyl, -(C1-C3)alkoxy, and (C3-C 10 )heterocyclo, (C3-C10)cycloalkyl, -(CH2)n-(C3-C 10 )Cycloalkyl, -(CH2)n-(C3-C 10 )heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 are attached together with atoms and nitrogen-containing (C3-C 10 ) form a heterocycle, and each of these contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R 7 is H, (C1-C3) alkyl, or R 7 and R 26It combines with the carbon atom it is bonded to to form a carbon-carbon double bond; R 8 , R 9 , R 10 , R 11 Each of these is independently H, halo, OH, cyano, (C1-C3)alkyl, (C1-C3)alkoxy, aryl, or heteroaryl, and each of these is one or more R allowed by valence. w The base, which can be optionally replaced; R 12 , R 13 , R 14 , R 15 These are H, NH2, (C1-C3) alkyl, and -N(R) respectively, independently. 5 )-(CH2)mN(R 5 )-XR 6 And, however, R 12 , R 13 , R 14 , and R 15 Three or fewer substituents are H, and each of them has one or more R atoms allowed by valence. w It can be arbitrarily substituted in the base; R 16 is NH2, or -N(R 5 )-(CH2) m -X-(CH2) n -R 6 And any of these allows one or more R by valence. w The base, which can be optionally replaced; R 17 is cyano, heteroaryl, -(CH2) m -C(O)OR 6 , or -N(R 5 )-(CH2) m -X-(CH2) n -R 6 And any of these allows one or more R by valence. w The base, which can be optionally replaced; R 18 , R 19 , R 20 , R 21Each of these is independently H, halo, (C1-C3)alkyl, (C1-C3)alkoxy, or -N(R) 5 )-XR 6 And, however, R 18 , R 19 , R 20 , R 21 Two or fewer substituents among them are H; or R 18 , R 19 They combine with the carbon to which they are attached, (C3-C 10 )Cycloalkyl or (C3-C 10 ) form a heterocycloid, or R 19 , R 20 They combine with the carbon to which they are attached, (C3-C 10 )Cycloalkyl or (C3-C 10 ) form a heterocycloid, or R 20 , R 21 They combine with the carbon to which they are attached, (C3-C 10 )Cycloalkyl or (C3-C 10 ) form heterocycloids, and each of these is allowed by one or more R atoms depending on their valence. w The base, which can be optionally replaced; R 25 These are aryl, heteroaryl, or (C3-C 10 ) are heterocycloidal, and each of these allows one or more R by valence w The base, which can be optionally replaced; R w Each instance independently consists of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkyl, while alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are halo, cyano, oxo (C3-C10 ) Heterocyclo, (C3-C 10 )Cycloalkyl, -(CH2) n -(C3-C 10 )Cycloalkyl, -(CH2) n -(C3-C 10 ) Heterocyclo, -(CH2) n -Aryl, -(CH2) n -It can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls; X is a bonding group, -SO2-, -(CH2) n C(O)(CH2) m -, -C(O)NH-, -C(O)N(R) w )-, -NHC(O)NH-, or -(CH2) n -and; Y1 is -NHR 25 ,-NHC(O)R 25 , or -CHR 25 R 26 and; m is 0, 1, 2, 3, or 4; k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n is 0, 1, 2, 3, or 4.

[0130] In one embodiment, L is -L b -(L a ) t - (In the formula, at each occurrence, L a The binding group is CR. 5 R 6 , C(R 5 R 6 )O, C(R 5 R 6 )C(R 5 R 6 )O, SO2, NR 5 , C(R 5 R 6 )NR 5 SO2NR 5 , SONR 5 CONR 5 , NR 5 CONR 6 , NR5 SO2NR 6 CO, CR 5 =CR 6 , C≡C, SiR 5 R 6 P(O)R 5 , P(O)OR 5 , NR 5 C(=NCN)NR 6 , NR 5 C (=NCN), and NR 5 C(=CNO2)NR 6 Independently selected from the group consisting of, each of these is one or more R allowed by valence. w The base, which can be optionally replaced; L b The following group is selected: [ka] t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0131] In one embodiment, L is -(CH2CH2)t-, -(CH2O)t-, or -(CH2CH2O)t-.

[0132] In one embodiment, A is part of formula XI, [ka] or a pharmaceutically acceptable salt thereof. (In the formula, R 22 H, halo, OH, -NR5R5, (C1-C3)alkyl, (C1-C3)alkoxy, (hydroxy)(C1-C3)alkyl, cyano, -N(R 5 )-XR 6 , -N(R 5 )-(CH2)mN(R 5 )-XR 6 aryl, or heteroaryl, and any of these is allowed by valence to contain one or more R w The base, which can be optionally replaced; R 23 H, Halo, OH, -NR 5 R 5 ,-(CH2) n -NR 5 R 5 (C1-C3)alkyl, (C1-C3)alkoxy, -C(O)NR 5 R 6 (Hydroxy)(C1-C3)alkyl, cyano, -N(R 5 )-XR 6 , -N(R 5 )-(CHR 5 )mXR 6 , -N(R 5 )-(CH2)mN(R 5 )-XR 6 , aryl, heteroaryl, or R 22 and R 23 It attaches together with the carbon that it is bonded to, (C3-C 10 )Cycloalkyl ring or (C3-C 10 ) Forming a heterocyclic ring, each of which contains one or more R atoms allowed by valence w The base, which can be optionally replaced; R 24 H, halo, OH, -NR5R5, -(CH2)n-NR5R5, (C1-C3)alkyl, (C1-C3)alkoxy, (halo)(C1-C3)alkyl, (hydroxy)(C1-C3)alkyl, cyano, -NO2, -N(R 5 )-XR 6 , -N(R 5 )-(CH2)mN(R 5 )-XR 6 , aryl, heteroaryl, or R 23 and R 24 They combine with the carbon to which they are attached, (C3-C 10 )Cycloalkyl ring or (C3-C 10 ) form a heterocycle, and each of these contains one or more R atoms allowed by valence. w It can be optionally substituted by the base; R 5Each instance independently produces H, (C1-C3) alkyl, and (C3-C 10 ) Heterocyclo, (C3-C 10 )Cycloalkyl, -(CH2) n -(C3-C 10 )Cycloalkyl, -(CH2) n -(C3-C 10 ) Heterocyclo, -(CH2) n -Aryl, -(CH2) n -A heteroaryl, aryl, or heteroaryl, each of which contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R 6 Each instance independently produces OH, (C1-C3)alkyl, -(C1-C3)alkoxy, and (C3-C 10 )heterocyclo, (C3-C10)cycloalkyl, -(CH2)n-(C3-C 10 )Cycloalkyl, -(CH2)n-(C3-C 10 )heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 are attached together with atoms and nitrogen-containing (C3-C 10 ) form a heterocycle, and each of these contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R w Each instance independently consists of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkyl, while alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are halo, cyano, oxo (C3-C 10 ) Heterocyclo, (C3-C 10 )Cycloalkyl, -(CH2) n-(C3-C 10 )Cycloalkyl, -(CH2) n -(C3-C 10 ) Heterocyclo, -(CH2) n -Aryl, -(CH2) n -It can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls; X is a bonding group, -SO2-, -(CH2) n C(O)(CH2) m -, -C(O)NH-, -C(O)N(R) w )-, -NHC(O)NH-, or -(CH2) n -and; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4.

[0133] In one embodiment, R 22 H is; R 23 H is R 24 It is a halo.

[0134] In one embodiment, A is a part of formula XII, XIII, XIV, XV, XVI, XVII, or XVIII. [ka] or a pharmaceutically acceptable salt thereof. (In the formula, R 28 , R 29 , R 30 , R 31 These are independently H, Halogen, OH, and -NR. 5 R 5 ,-(CH2)n-NR 5 R 5 (C1-C3)alkyl, (C1-C3)alkoxy, (halo)(C1-C3)alkyl, (hydroxy)(C1-C3)alkyl, cyano, -NO2, -N(R) 5 )-XR 6 , -N(R 5 )-(CH2)mN(R 5 )-XR6 , aryl, heteroaryl, or R 28 , R 29 They combine with the carbon to which they are attached, (C3-C 10 )Cycloalkyl or (C3-C 10 ) form a heterocycloid, or R 30 , R 31 They combine with the carbon to which they are attached, (C3-C 10 )Cycloalkyl or (C3-C 10 ) form a heterocycloid, or R 29 , R 30 They either combine to form a bonding group, or R 29 , R 30 They combine with the carbon to which they are attached, (C3-C 10 )Cycloalkyl or (C3-C 10 ) Forming heterocyclo, aryl, or heteroaryl atoms, each of which contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R 5 Each instance independently produces H, (C1-C3) alkyl, and (C3-C 10 ) Heterocyclo, (C3-C 10 )Cycloalkyl, -(CH2) n -(C3-C 10 )Cycloalkyl, -(CH2) n -(C3-C 10 ) Heterocyclo, -(CH2) n -Aryl, -(CH2) n -A heteroaryl, aryl, or heteroaryl, each of which contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R 6 Each instance independently produces OH, (C1-C3)alkyl, -(C1-C3)alkoxy, and (C3-C 10 )heterocyclo, (C3-C10)cycloalkyl, -(CH2)n-(C3-C 10 )Cycloalkyl, -(CH2)n-(C3-C 10)heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 are attached together with atoms and nitrogen-containing (C3-C 10 ) form a heterocycle, and each of these contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R w Each instance independently consists of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkyl, while alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are halo, cyano, oxo (C3-C 10 ) Heterocyclo, (C3-C 10 )Cycloalkyl, -(CH2) n -(C3-C 10 )Cycloalkyl, -(CH2) n -(C3-C 10 ) Heterocyclo, -(CH2) n -Aryl, -(CH2) n -It can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls; X is a bonding group, -SO2-, -(CH2) n C(O)(CH2) m -, -C(O)NH-, -C(O)N(R) w )-, -NHC(O)NH-, or -(CH2) n -and; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4.

[0135] Linker L1 and L Linkers L1 and L are independently covalently bonded to the E3 ubiquitin ligase binding moiety A, respectively. Linker L is also independently covalently bonded to the target protein binding moiety Q. The covalent bonding of the links is preferably via an amide, ester, thioester, keto group, carbamate (urethane), carbon, or ether, each of which can be inserted at any site in the A or Q moiety that is valence-permissible, such as any substituent or functional group in the A or Q moiety. In certain preferred embodiments, the linkers may optionally be substituted with (C1-C6)alkyl, (C1-C6)alkylene, (C1-C6)alkyne, aryl, heteroaryl, (C3-C8)cycloalkyl, or (C3-C8)heterocyclo. In one embodiment, linker L1 or L is R as defined above. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , or R 31 It is connected to part A via [a certain mechanism].

[0136] In one embodiment, L1 is -L b -(L a ) t It is -H, where H is hydrogen.

[0137] In one embodiment, L is -L b -(L a ) t- That is the case.

[0138] In one embodiment, t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0139] In one embodiment, L a The group is selected from the following: [ka] JPEG2026143564000016.jpg241160JPEG2026143564000017.jpg235161L b The following group is selected: [ka] t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0140] Embodiments A-L1 In one embodiment, the compound having general formula A-L1 is selected from the compounds listed in Table 1. [Table 1] TIFF2026143564000020.tif196162TIFF2026143564000021.tif215162TIFF2026143564000022.tif218162TIFF2026143564000023.tif194162TIFF2026143564000024.tif208162TIFF2026143564000025.tif219162TIFF2026143564000026.tif198162TIFF2026143564000027.tif198162TIFF2026143564000028.tif218162TIFF2026143564000029.tif168162TIFF2026143564000030.tif199162TIFF2026143564000031.tif193162TIFF2026143564000032.tif228162TIFF2026143564000033.tif203162TIFF2026143564000034.tif210162TIFF2026143564000035.tif198162TIFF2026143564000036.tif222162TIFF2026143564000037.tif202162TIFF2026143564000038.tif219162TIFF2026143564000039.tif221162TIFF2026143564000040.tif210162TIFF2026143564000041.tif143162TIFF2026143564000042.tif188162TIFF2026143564000043.tif212162TIFF2026143564000044.tif208162TIFF2026143564000045.tif198162TIFF2026143564000046.tif202162TIFF2026143564000047.tif184162TIFF2026143564000048.tif179162TIFF2026143564000049.tif199162TIFF2026143564000050.tif218162TIFF2026143564000051.tif186162TIFF2026143564000052.tif193162 TIFF2026143564000053.tif48162

[0141] (A) k -LQ Embodiment In one embodiment, general formula (A) k Compounds containing -LQ are selected from the compounds listed in Table 2, Table 3, or Table 4. [Table 2] TIFF2026143564000055.tif203162TIFF2026143564000056.tif193162TIFF2026143564000057.tif201162TIFF2026143564000058.tif223162TIFF2026143564000059.tif212162TIFF2026143564000060.tif207162TIFF2026143564000061.tif207162TIFF2026143564000062.tif202162TIFF2026143564000063.tif224162TIFF2026143564000064.tif214162TIFF2026143564000065.tif229162TIFF2026143564000066.tif209162TIFF2026143564000067.tif205162TIFF2026143564000068.tif221162TIFF2026143564000069.tif208162TIFF2026143564000070.tif220162TIFF2026143564000071.tif213162TIFF2026143564000072.tif210162TIFF2026143564000073.tif189162TIFF2026143564000074.tif211162TIFF2026143564000075.tif189162TIFF2026143564000076.tif204162TIFF2026143564000077.tif199162TIFF2026143564000078.tif202162TIFF2026143564000079.tif203162TIFF2026143564000080.tif184162TIFF2026143564000081.tif206162TIFF2026143564000082.tif104162 [Table 3] TIFF2026143564000084.tif147162TIFF2026143564000085.tif191162TIFF2026143564000086.tif210162TIFF2026143564000087.tif161162TIFF2026143564000088.tif189162TIFF2026143564000089.tif182162TIFF2026143564000090.tif210162TIFF2026143564000091.tif189162TIFF2026143564000092.tif172162TIFF2026143564000093.tif190162TIFF2026143564000094.tif161162TIFF2026143564000095.tif181162TIFF2026143564000096.tif184162TIFF2026143564000097.tif155162TIFF2026143564000098.tif197162TIFF2026143564000099.tif171162TIFF2026143564000100.tif164162TIFF2026143564000101.tif229162TIFF2026143564000102.tif200162TIFF2026143564000103.tif152162TIFF2026143564000104.tif188162TIFF2026143564000105.tif199162TIFF2026143564000106.tif178162TIFF2026143564000107.tif170162TIFF2026143564000108.tif198162TIFF2026143564000109.tif153162TIFF2026143564000110.tif177162TIFF2026143564000111.tif227162TIFF2026143564000112.tif191162TIFF2026143564000113.tif171162TIFF2026143564000114.tif179162TIFF2026143564000115.tif212162TIFF2026143564000116.tif198162TIFF2026143564000117.tif188162TIFF2026143564000118.tif186162TIFF2026143564000119.tif178162TIFF2026143564000120.tif177162TIFF2026143564000121.tif175162TIFF2026143564000122.tif140162TIFF2026143564000123.tif199162TIFF2026143564000124.tif210162TIFF2026143564000125.tif195162TIFF2026143564000126.tif164162TIFF2026143564000127.tif178162TIFF2026143564000128.tif211162TIFF2026143564000129.tif223162TIFF2026143564000130.tif207162TIFF2026143564000131.tif157162TIFF2026143564000132.tif204162TIFF2026143564000133.tif164162TIFF2026143564000134.tif121162TIFF2026143564000135.tif203162TIFF2026143564000136.tif145162TIFF2026143564000137.tif204162TIFF2026143564000138.tif178162TIFF2026143564000139.tif203162TIFF2026143564000140.tif206162TIFF2026143564000141.tif197162TIFF2026143564000142.tif197162TIFF2026143564000143.tif227162TIFF2026143564000144.tif152162TIFF2026143564000145.tif169162TIFF2026143564000146.tif184162TIFF2026143564000147.tif113162TIFF2026143564000148.tif219162TIFF2026143564000149.tif162162TIFF2026143564000150.tif122162TIFF2026143564000151.tif220162TIFF2026143564000152.tif163162TIFF2026143564000153.tif210162TIFF2026143564000154.tif214162TIFF2026143564000155.tif199162TIFF2026143564000156.tif215162TIFF2026143564000157.tif165162TIFF2026143564000158.tif175162TIFF2026143564000159.tif173162TIFF2026143564000160.tif220162TIFF2026143564000161.tif203162TIFF2026143564000162.tif169162TIFF2026143564000163.tif204162TIFF2026143564000164.tif172162TIFF2026143564000165.tif198162TIFF2026143564000166.tif182162TIFF2026143564000167.tif184162TIFF2026143564000168.tif146162TIFF2026143564000169.tif154162TIFF2026143564000170.tif193162TIFF2026143564000171.tif183162TIFF2026143564000172.tif184162TIFF2026143564000173.tif154162TIFF2026143564000174.tif215162TIFF2026143564000175.tif214162TIFF2026143564000176.tif163162TIFF2026143564000177.tif162162TIFF2026143564000178.tif228162TIFF2026143564000179.tif224162TIFF2026143564000180.tif213162TIFF2026143564000181.tif225162TIFF2026143564000182.tif216162TIFF2026143564000183.tif224162TIFF2026143564000184.tif20616 2TIFF2026143564000185.tif223162TIFF2026143564000186.tif64162Table 4: General formula AL. b -L a -Q embodiment In some embodiments, the compounds of the present invention are of the general formula AL b -L a -Q has, in the formula, part A, L b , and L a -Q is selected independently from Table 4. A and L are listed in Table 4. b , and L a Any combination of -Q is intended to be the compound of the present invention. b L is connected to a portion of A via covalent bonds at any position of A permitted by valence. a 1.0-6 are the seven L's a 1. The formula includes a part where T is 0, 1, 2, 3, 4, 5, or 6, respectively. Similarly, L a 2.0-5 are six L a It includes two parts, where T is 0, 1, 2, 3, 4, or 5, respectively; L b 6.1-3 each contain three Lb6 moieties having one, two, or three methylene chains; L b 7.0-5 consists of six L units, each having 0, 1, 2, 3, 4, or 5 methylene chains. b Includes 7 parts; L b 8.1-4 contains four L molecules, each having 1, 2, 3, or 4 methylene chains. b Includes 8 parts. R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R45 、R 46 、R 47 、R 48 、R 49 、R 50 、R 51 、R 52 、R 53 、R 54 、R 55 、R 56 、R 57 、R 58 、R 59 、R 60 、R 61 、R 62 、R 63 、R 64 、R 65 、R 66 、R 67 、R 68 、R 69 、R 70 、R 71 、R 72 、R 73 、R 74 、R 75 、R 76 、R 77 、R 78 、R 79 、R 80 、R 81 、R 82 、R 83 、R 84 、R 85 、R 86 、R 87 、R 88 、R 89 、R 90 、R 91 、R 92 、R 93 、R 94 、R 95 、R 96 、R 97 、R 98 、R 99 、R 100 、R 101 、R 102 、R 103 、R 104 、およびR 105Each is independently selected from the group consisting of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl, and alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are halo, cyano, oxo (C3-C 10 ) Heterocyclo, (C3-C 10 )Cycloalkyl, -(CH2) n -(C3-C 10 )Cycloalkyl, -(CH2) n -(C3-C 10 ) Heterocyclo, -(CH2) n -Aryl, -(CH2) n -It can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls. In one embodiment, L b R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 60 , R 61 , R62 , R 63 , R 64 , R 65 , R 66 , R 67 , R 68 , R 69 , R 70 , R 71 , R 72 , R 73 , R 74 , R 75 , R 76 , R 77 , R 78 , R 79 , R 80 , R 81 , R 82 , R 83 , R 84 , R 85 , R 86 , R 87 , R 88 , R 89 , R 90 , R 91 , R 92 , R 93 , R 94 , R 95 , R 96 , R 97 , R 98 , R 99 , R 100 , R 101 , R 102 , R 103 , R 104 , or R 105 is covalently linked to the moiety A via

[0142] In one embodiment, the compound is 4.001-L b 1-L a 1.0-6, 4.001-L b 1-L a 2.0-5, 4.002-L b 1-L a 1.0-6, 4.002-L b 1-L a 2.0-5, 4.003-L b 1-L a 1.0-6, 4.003-L b 1-L a 2.0-5, 4.004-Lb 1-L a 1.0-6, 4.004-L b 1-L a 2.0-5, 4.005-L b 1-L a 1.0-6, 4.005-L b 1-L a 2.0-5, 4.006-L b 1-L a 1.0-6, 4.006-L b 1-L a 2.0-5, 4.007-L b 1-L a 1.0-6, 4.007-L b 1-L a 2.0-5, 4.008-L b 1-L a 1.0-6, 4.008-L b 1-L a 2.0-5, 4.009-L b 1-L a 1.0-6, 4.009-L b 1-L a 2.0-5, 4.010-L b 1-L a 1.0-6, 4.010-L b 1-L a 2.0-5, 4.011-L b 1-L a 1.0-6, 4.011-L b 1-L a 2.0-5, or 4.012-L b 1-L a It has a structure of 2.0-5.

[0143] In one embodiment, the compound is 4.001-L b 2-L a 1.0-6, 4.001-L b 2-L a 2.0-5, 4.002-L b 2-L a 1.0-6, 4.002-L b 2-L a 2.0-5, 4.003-L b 2-L a 1.0-6, 4.003-L b 2-La 2.0-5, 4.004-L b 2-La1.0-6, 4.004-L b 2-L a 2.0-5, 4.005-L b 2-L a 1.0-6, 4.005-L b 2-L a 2.0-5, 4.006-L b 2-L a 1.0-6, 4.006-L b 2-L a 2.0-5, 4.007-L b 2-L a 1.0-6, 4.007-L b 2-L a 2.0-5, 4.008-L b 2-L a 1.0-6, 4.008-L b 2-L a 2.0-5, 4.009-L b 2-L a 1.0-6, 4.009-L b 2-La2.0-5, 4.010-L b 2-L a 1.0-6, 4.010-L b 2-L a 2.0-5, 4.011-L b 2-L a 1.0-6, 4.011-L b 2-L a 2.0-5, or 4.012-L b 2-L a It has a structure of 2.0-5.

[0144] In one embodiment, the compound is 4.001-L b 3-L a 1.0-6, 4.001-L b 3-L a 2.0-5, 4.002-L b 3-L a 1.0-6, 4.002-L b 3-L a 2.0-5, 4.003-L b 3-L a 1.0-6, 4.003-L b3-L a 2.0-5, 4.004-L b 3-La 1.0-6, 4.004-L b 3-L a 2.0-5, 4.005-L b 3-L a 1.0-6, 4.005-L b 3-L a 2.0-5, 4.006-L b 3-L a 1.0-6, 4.006-L b 3-L a 2.0-5, 4.007-L b 3-L a 1.0-6, 4.007-L b 3-L a 2.0-5, 4.008-L b 3-L a 1.0-6, 4.008-L b 3-L a 2.0-5, 4.009-L b 3-L a 1.0-6, 4.009-L b 3-L a 2.0-5, 4.010-L b 3-L a 1.0-6, 4.010-L b 3-L a 2.0-5, 4.011-L b 3-L a 1.0-6, 4.011-L b 3-L a 2.0-5, or 4.012-L b 3-L a It has the structure of 2.0-5.

[0145] In one embodiment, the compound is 4.001-L b 4-L a 1.0-6, 4.001-L b 4-L a 2.0-5, 4.002-L b 4-L a 1.0-6, 4.002-L b 4-L a 2.0-5, 4.003-L b 4-L a1.0-6, 4.003-L b 4-L a 2.0-5, 4.004-L b 4-L a 1.0-6, 4.004-L b 4-L a 2.0-5, 4.005-L b 4-L a 1.0-6, 4.005-L b 4-L a 2.0-5, 4.006-L b 4-L a 1.0-6, 4.006-L b 4-L a 2.0-5, 4.007-L b 4-L a 1.0-6, 4.007-L b 4-L a 2.0-5, 4.008-L b 4-L a 1.0-6, 4.008-L b 4-L a 2.0-5, 4.009-L b 4-L a 1.0-6, 4.009-L b 4-L a 2.0-5, 4.010-L b 4-L a 1.0-6, 4.010-L b 4-L a 2.0-5, 4.011-L b 4-L a 1.0-6, 4.011-L b 4-La having a structure of 2.0-5, or 4.012-L b 4-L a It has the structure of 2.0-5.

[0146] In one embodiment, the compound is 4.001-L b 5-L a 1.0-6, 4.001-L b 5-L a 2.0-5, 4.002-L b 5-L a 1.0-6, 4.002-L b 5-L a 2.0-5, 4.003-L b5~L a 1.0-6, 4.003-L b 5~L a 2.0-5, 4.004-L b 5~L a 1.0-6, 4.004-L b 5~L a 2.0-5, 4.005-L b 5~L a 1.0-6, 4.005-L b 5~L a 2.0-5, 4.006-L b 5~L a 1.0-6, 4.006-L b 5~L a 2.0-5, 4.007-L b 5~L a 1.0-6, 4.007-L b 5~L a 2.0-5, 4.008-L b 5~L a 1.0-6, 4.008-L b 5~L a 2.0-5, 4.009-L b 5~L a 1.0-6, 4.009-L b 5~L a 2.0-5, 4.010-L b 5~L a 1.0-6, 4.010-L b 5~L a 2.0-5, 4.011-L b 5~L a 1.0-6, 4.011-L b 5~L a 2.0-5 or 4.012-L b 5~L a It has a structure of 2.0-5.

[0147] In one embodiment, the compound is 4.001-L b 6~L a 1.0-6, 4.001-L b 6~L a 2.0-5, 4.002-L b 6~L a 1.0-6, 4.002-L b 6~L a2.0-5, 4.003-L b 6~L a 1.0-6, 4.003-L b 6~L a 2.0-5, 4.004-L b 6~L a 1.0-6, 4.004-L b 6~L a 2.0-5, 4.005-L b 6~L a 1.0-6, 4.005-L b 6~L a 2.0-5, 4.006-L b 6~L a 1.0-6, 4.006-L b 6~L a 2.0-5, 4.007-L b 6~L a 1.0-6, 4.007-L b 6~L a 2.0-5, 4.008-L b 6~L a 1.0-6, 4.008-L b 6~L a 2.0-5, 4.009-L b 6~L a 1.0-6, 4.009-L b 6~L a 2.0-5, 4.010-L b 6~L a 1.0-6, 4.010-L b 6~L a 2.0-5, 4.011-L b 6~L a 1.0-6, 4.011-L b 6~L a 2.0-5, or 4.012-L b 6~L a It has a structure of 2.0-5.

[0148] In one embodiment, the compound is 4.001-L b 7~L a 1.0-6, 4.001-L b 7~L a 2.0-5, 4.002-L b 7~L a 1.0-6, 4.002-Lb 7 to L a 2.0-5, 4.003-L b 7 to L a 1.0-6, 4.003-L b 7 to L a 2.0-5, 4.004-L b 7 to L a 1.0-6, 4.004-L b 7 to L a 2.0-5, 4.005-L b 7 to L a 1.0-6, 4.005-L b 7 to L a 2.0-5, 4.006-L b 7 to L a 1.0-6, 4.006-L b 7 to L a 2.0-5, 4.007-L b 7 to L a 1.0-6, 4.007-L b 7 to L a 2.0-5, 4.008-L b 7 to L a 1.0-6, 4.008-L b 7 to L a 2.0-5, 4.009-L b 7 to L a 1.0-6, 4.009-L b 7 to L a 2.0-5, 4.010-L b 7 to L a 1.0-6, 4.010-L b 7 to L a 2.0-5, 4.011-L b 7 to L a 1.0-6, 4.011-L b 7 to L a 2.0-5, or 4.012-L b 7 to L a It has the structure of 2.0-5.

[0149] In one embodiment, the compound is 4.001-L b 8 to L a 1.0-6, 4.001-L b 8 to L a 2.0-5, 4.002-L b 8 to La 1.0-6, 4.002-L b 8~La2.0-5, 4.003-L b 8~L a 1.0-6, 4.003-L b 8~L a 2.0-5, 4.004-L b 8~L a 1.0-6, 4.004-L b 8~L a 2.0-5, 4.005-L b 8~L a 1.0-6, 4.005-L b 8~L a 2.0-5, 4.006-L b 8~L a 1.0-6, 4.006-L b 8~L a 2.0-5, 4.007-L b 8~L a 1.0-6, 4.007-L b 8~L a 2.0-5, 4.008-L b 8~L a 1.0-6, 4.008-L b 8~L a 2.0-5, 4.009-L b 8~L a 1.0-6, 4.009-L b 8~L a 2.0-5, 4.010-L b 8~L a 1.0-6, 4.010-L b 8~L a 2.0-5, 4.011-L b 8~L a 1.0-6, 4.011-L b 8~L a 2.0-5, or 4.012-L b 8~L a It has a structure of 2.0-5.

[0150] In one embodiment, the compound is 4.001-L b 9~L a 1.0-6, 4.001-L b 9~L a 2.0-5, 4.002-Lb 9~L a 1.0-6, 4.002-L b 9~L a 2.0-5, 4.003-L b 9~L a 1.0-6, 4.003-L b 9~L a 2.0-5, 4.004-L b 9~L a 1.0-6, 4.004-L b 9~L a 2.0-5, 4.005-L b 9~L a 1.0-6, 4.005-L b 9~L a 2.0-5, 4.006-L b 9~L a 1.0-6, 4.006-L b 9~L a 2.0-5, 4.007-L b 9~L a 1.0-6, 4.007-L b 9~L a 2.0-5, 4.008-L b 9~L a 1.0-6, 4.008-L b 9~L a 2.0-5, 4.009-L b 9~L a 1.0-6, 4.009-L b 9~L a 2.0-5, 4.010-L b 9~L a 1.0-6, 4.010-L b 9~L a 2.0-5, 4.011-L b 9~L a 1.0-6, 4.011-L b 9~L a 2.0-5, or 4.012-L b 9~L a It has a structure of 2.0-5.

[0151] In one embodiment, the compound is 4.001-L b 10~L a 1.0-6, 4.001-L b10~L a 2.0-5, 4.002-L b 10~L a 1.0-6, 4.002-L b 10~L a 2.0-5, 4.003-L b 10~L a 1.0-6, 4.003-L b 10~L a 2.0-5, 4.004-L b 10~L a 1.0-6, 4.004-L b 10~L a 2.0-5, 4.005-L b 10~L a 1.0-6, 4.005-L b 10~L a 2.0-5, 4.006-L b 10~L a 1.0-6, 4.006-L b 10~L a 2.0-5, 4.007-L b 10~L a 1.0-6, 4.007-L b 10~L a 2.0-5, 4.008-L b 10~L a 1.0-6, 4.008-L b 10~L a 2.0-5, 4.009-L b 10~L a 1.0-6, 4.009-L b 10~L a 2.0-5, 4.010-L b 10~L a 1.0-6, 4.010-L b 10~L a 2.0-5, 4.011-L b 10~L a 1.0-6, 4.011-L b 10~L a 2.0-5, or 4.012-L b 10~L a has the structure of 2.0-5.

[0152] In one embodiment, the compound is 4.001-Lb 11~L a 1.0-6, 4.001-L b 11~L a 2.0-5, 4.002-L b 11~L a 1.0-6, 4.002-L b 11~L a 2.0-5, 4.003-L b 11~L a 1.0-6, 4.003-L b 11~L a 2.0-5, 4.004-L b 11~L a 1.0-6, 4.004-L b 11~L a 2.0-5, 4.005-L b 11~L a 1.0-6, 4.005-L b 11~L a 2.0-5, 4.006-L b 11~L a 1.0-6, 4.006-L b 11~L a 2.0-5, 4.007-L b 11~L a 1.0-6, 4.007-L b 11~L a 2.0-5, 4.008-L b 11~L a 1.0-6, 4.008-L b 11~L a 2.0-5, 4.009-L b 11~L a 1.0-6, 4.009-L b 11~L a 2.0-5, 4.010-L b 11~L a 1.0-6, 4.010-L b 11~L a 2.0-5, 4.011-L b 11~L a 1.0-6, 4.011-L b 11~L a 2.0-5, or 4.012-L b 11~L a It has the structure of 2.0-5.

[0153] In one embodiment, the compound is 4.001-L b 12~L a 1.0-6, 4.001-L b 12~L a 2.0-5, 4.002-L b 12~L a 1.0-6, 4.002-L b 12~L a 2.0-5, 4.003-L b 12~L a 1.0-6, 4.003-L b 12~L a 2.0-5, 4.004-L b 12~L a 1.0-6, 4.004-L b 12~L a 2.0-5, 4.005-L b 12~L a 1.0-6, 4.005-L b 12~L a 2.0-5, 4.006-L b 12~L a 1.0-6, 4.006-L b 12~L a 2.0-5, 4.007-L b 12~L a 1.0-6, 4.007-L b 12~L a 2.0-5, 4.008-L b 12~L a 1.0-6, 4.008-L b 12~L a 2.0-5, 4.009-L b 12~L a 1.0-6, 4.009-L b 12~L a 2.0-5, 4.010-L b 12~L a 1.0-6, 4.010-L b 12~L a 2.0-5, 4.011-L b 12~L a 1.0-6, 4.011-L b 12~L a 2.0-5, or 4.012-Lb 12~L a It has a structure of 2.0-5.

[0154] In one embodiment, the compound is 4.001-L b 13~L a 1.0-6, 4.001-L b 13~L a 2.0-5, 4.002-L b 13~L a 1.0-6, 4.002-L b 13~L a 2.0-5, 4.003-L b 13~L a 1.0-6, 4.003-L b 13~L a 2.0-5, 4.004-L b 13~L a 1.0-6, 4.004-L b 13~L a 2.0-5, 4.005-L b 13~L a 1.0-6, 4.005-L b 13~L a 2.0-5, 4.006-L b 13~L a 1.0-6, 4.006-L b 13~L a 2.0-5, 4.007-L b 13~L a 1.0-6, 4.007-L b 13~L a 2.0-5, 4.008-L b 13~L a 1.0-6, 4.008-L b 13~L a 2.0-5, 4.009-L b 13~L a 1.0-6, 4.009-L b 13~L a 2.0-5, 4.010-L b 13~L a 1.0-6, 4.010-L b 13~L a 2.0-5, 4.011-L b 13~L a1.0-6, 4.011-L b 13~L a 2.0-5, or 4.012-L b 13~L a It has a structure of 2.0-5.

[0155] In one embodiment, the compound is 4.001-L b 14~L a 1.0-6, 4.001-L b 14~L a 2.0-5, 4.002-L b 14~L a 1.0-6, 4.002-L b 14~L a 2.0-5, 4.003-L b 14~L a 1.0-6, 4.003-L b 14~L a 2.0-5, 4.004-L b 14~L a 1.0-6, 4.004-L b 14~L a 2.0-5, 4.005-L b 14~L a 1.0-6, 4.005-L b 14~L a 2.0-5, 4.006-L b 14~L a 1.0-6, 4.006-L b 14~L a 2.0-5, 4.007-L b 14~L a 1.0-6, 4.007-L b 14~L a 2.0-5, 4.008-L b 14~L a 1.0-6, 4.008-L b 14~L a 2.0-5, 4.009-L b 14~L a 1.0-6, 4.009-L b 14~L a 2.0-5, 4.010-L b 14~L a 1.0-6, 4.010-L b 14~La 2.0-5, 4.011-L b 14~L a 1.0-6, 4.011-L b 14~L a 2.0-5, or 4.012-L b 14~L a It has a 2.0-5 structure. [Table 4] TIFF2026143564000188.tif235162TIFF2026143564000189.tif234162 TIFF2026143564000190.tif236162TIFF2026143564000191.tif236162TIFF2026143564000192.tif235162TIFF2026143564000193.tif236162 [Table 5] TIFF2026143564000195.tif239162TIFF2026143564000196.tif239162TIFF2026143564000197.tif239162 TIFF2026143564000198.tif239162 TIFF2026143564000199.tif238162TIFF2026143564000200.tif238162TIFF2026143564000201.tif239162 TIFF2026143564000202.tif239162TIFF2026143564000203.tif240162TIFF2026143564000204.tif238162 TIFF2026143564000205.tif240162TIFF2026143564000206.tif238162TIFF20261435640 00207.tif239162TIFF2026143564000208.tif240162TIFF2026143564000209.tif240162 TIFF2026143564000210.tif238162TIFF2026143564000211.tif241162TIFF20261435640 00212.tif241162TIFF2026143564000213.tif241162TIFF2026143564000214.tif241162 TIFF2026143564000215.tif241162TIFF2026143564000216.tif241162TIFF20261435640 00217.tif241162TIFF2026143564000218.tif241162TIFF2026143564000219.tif241162 TIFF2026143564000220.tif241162TIFF2026143564000221.tif241162TIFF20261435640 00222.tif241162TIFF2026143564000223.tif239162TIFF2026143564000224.tif239162

[0156] In one embodiment, part A is selected from the compounds listed in Table 6 of Example 6.

[0157] In one embodiment, part A is selected from the following group: 3-[1-oxo-5-(quinazoline-4-ylamino)isoindoline-2-yl]piperidine-2,6-dione; 3-[5-[(4-aminothieno[2,3-d]pyrimidine-2-yl)amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; N-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindorin-5-yl]acetamide; 3-[5-[(2-aminopyrimidine-4-yl)amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 6-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindoline-5-yl]amino]pyridazine-3-carbonitrile; 3-[[2-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindoline-5-yl]aminoacetyl]aminobenzamide; 2-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindorin-5-yl]aminoacetic acid; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]quinoline-2-carboxamide; 3-[6-[[2-(2-methyl-1-piperidyl)-2-oxo-ethyl]amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 3-[6-[(2-isoindoline-2-yl-2-oxo-ethyl)amino]-1-oxo-isoindoline-2-yl]piperidine-2,6-dione; N-(cyclopropylmethyl)-2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]amino]-N-methylacetamide; Acetic acid; 3-[1-oxo-6-(quinazoline-4-ylamino)isoindoline-2-yl]piperidine-2,6-dione; 3-[6-[[2-(3-methyl-1-piperidyl)-2-oxo-ethyl]amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 3-[6-[(4-methyl-3-oxopyrazine-2-yl)amino]-1-oxoisoindorin-2-yl]piperidine-2,6-dione; 3-[1-oxo-6-(quinoxaline-2-ylamino)isoindoline-2-yl]piperidine-2,6-dione; 3-[6-[(1-methylpyrazolo[3,4-d]pyrimidine-4-yl)amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 3-[6-(5,7-dihydrofl[3,4-d]pyrimidine-2-ylamino)-1-oxoisoindorin-2-yl]piperidine-2,6-dione; 3-[6-[(6-methylpyrimidine-4-yl)amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]amino]-N-phenyl-acetamide; 3-[6-[[2-(2,4-dimethylpiperazine-1-yl)-2-oxo-ethyl]amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 3-[6-(dimethylamino)-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 3-(1-oxo-6-phenyl-isoindoline-2-yl)piperidine-2,6-dione; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]amino]-N,N-dimethylacetamide; 3-[6-[[2-(2-methylmorpholine-4-yl)-2-oxo-ethyl]amino]-1-oxo-isoindoline-2-yl]piperidine-2,6-dione; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]amino]-N-methyl-N-[(1-methylpyrazole-4-yl)methyl]acetamide; N-benzyl-2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]aminoacetamide; 6-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]amino]pyridazine-3-carbonitrile; 3-[6-[(6-methylpyrrolo[3,2-d]pyrimidine-4-yl)amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 2-(dimethylamino)-N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]acetamide; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]-5H-pyrrolo[2,3-b]pyridine-4-carboxamide; N-Cyclopropyl-2-[[2-(2,6-Dioxo-3-Piperidyl)-3-Oxo-Isoindorin-5-yl]aminoacetamide; 3-[1-oxo-6-(2-oxoimidazolidine-1-yl)isoindorin-2-yl]piperidine-2,6-dione; 2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorine-5-carbonitrile; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]amino]propanoic acid; 2-Acetamide-N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]acetamide; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]aminoacetamide; 3-[6-[[2-(3-methyl-5-oxopiperazine-1-yl)-2-oxo-ethyl]amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]acetamide; 3-[6-[[2-(4-methyl-3-oxopiperazine-1-yl)-2-oxo-ethyl]amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]-3H-imidazo[4,5-b]pyridine-6-carboxamide; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]amino]-N-tetrahydropyran-4-yl-acetamide; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]aminoacetic acid; 3-[1-oxo-6-[[2-oxo-2-(1-piperidyl)ethyl]amino]isoindorin-2-yl]piperidine-2,6-dione; 3-(1-oxo-7-phenyl-isoindoline-2-yl)piperidine-2,6-dione; 2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorine-4-carbonitrine; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-4-yl]aminoacetic acid; 3-(7-fluoro-1-oxo-isoindorin-2-yl)piperidine-2,6-dione; 3-(5-amino-1-oxo-3,4-dihydroisoquinoline-2-yl)piperidine-2,6-dione; t-butyl 2-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-1-yl]acetate; 3-[1-(2H-indole-3-yl)-3-oxo-isoindorin-2-yl]piperidine-2,6-dione; 2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-1-carbonitrile; 3-[1-(dimethylamino)-3-oxo-isoindorin-2-yl]piperidine-2,6-dione; 3-(2-oxopyrrolidine-1-yl)piperidine-2,6-dione; 3-(Quinazoline-2-ylamino)piperidine-2,6-dione; (3Z)-3-benzylidenepiperidine-2,6-dione; 3-(Quinoxaline-2-ylamino)piperidine-2,6-dione; 3-(pyrimidine-2-ylamino)piperidine-2,6-dione; N-(2,6-dioxo-3-piperidyl)-2-oxo-3H-pyridine-6-carboxamide; 3-(4-methyl-1,1,3-trioxo-1,2-benzothiazole-2-yl)piperidine-2,6-dione; 3-(8-amino-4-oxo-1,2,3-benzotriazin-3-yl)piperidine-2,6-dione; 3-(5-amino-4-oxo-1,2,3-benzotriazin-3-yl)piperidine-2,6-dione; 3-(4-oxo-1,2,3-benzotriazin-3-yl)piperidine-2,6-dione; 3-(5-methyl-4-oxo-1,2,3-benzotriazin-3-yl)piperidine-2,6-dione; 3-(6-methyl-4-oxo-1,2,3-benzotriazin-3-yl)piperidine-2,6-dione; and 3-(8-methyl-4-oxo-1,2,3-benzotriazin-3-yl)piperidine-2,6-dione.

[0158] Target protein binding site Q The target proteins bound by partial Q are numerous in type and are selected from proteins expressed intracellularly such that at least a portion of their sequence is found within the cell. The term “protein” includes oligopeptide and polypeptide sequences of sufficient length to bind to partial Q according to the present invention. As otherwise described herein, any protein within a eukaryotic or microbial system, such as a virus, bacterium, or fungus, is a target for ubiquitination mediated by the compounds according to the present invention. Preferably, the target protein is a eukaryotic protein.

[0159] The Q portion of the present invention includes, for example, any portion that specifically binds to a protein (bounds to a target protein), and includes, in non-limiting examples, small target protein portions such as: in particular, Hsp90 inhibitors, kinase inhibitors, HDM2 and MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, nuclear hormone receptor compounds, immunosuppressive compounds, and compounds targeting aryl hydrocarbon receptors (AHRs). Some members of these types of small target protein binding portions are illustrated below. Such small target protein binding portions also include pharmaceutically acceptable salts, enantiomers, solvates, and their polymorphs. These binding portions are linked to a ubiquitin ligase binding portion via a linker to present the target protein (to which the protein target portion is bound) near a ubiquitin ligase for ubiquitination and degradation. In one embodiment, the ubiquitin ligase is cereblon.

[0160] Any protein capable of binding to partial Q and acting on or being degraded by ubiquitin ligases is a target protein according to the present invention. Generally, target proteins include structural proteins, receptors, enzymes, cell surface proteins, proteins related to cellular integration functions, such as proteins involved in catalytic activity, aromatase activity, motility, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulatory activity, signal transducer activity, structural molecular activity, binding activity (proteins, lipids, carbohydrates), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, and cell differentiation. These may include proteins involved in stimulus response, behavioral proteins, cell adhesion proteins, proteins involved in cell death, and proteins involved in transport (protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretory activity, electron transporter activity, pathogenesis, chaperone regulatory activity, nucleic acid binding activity, transcriptional regulator activity, extracellular tissue and biosynthetic activity, and translational regulatory factor activity). The target proteins may include, among other things, eukaryotes and prokaryotes such as humans and other animals such as livestock as targets for drug therapy, microorganisms for determining targets for antibiotics and other antimicrobial agents and plants, and even viruses.

[0161] In one embodiment, the target proteins are B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, Bcl, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, and PDE IV phosphodiesterase type 4, PDEI, PDEII, PDEIII, squalene-hopencyclase, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein, Gq, histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosome, glycogen phosphorylase, carbonate anhydrase, chemokine receptor, JAW / STAT, retinoid X receptor, HIV1 protease, HIV1 integrase, influenza, neuramimidase, hepatitis B reverse transcriptase, sodium channel, protein P-glycoprotein (and MRP), tyrosine kinase, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alpha, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, neukinin and receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, Ras / Raf / ME / ERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, c-Kit, TGFβ-activated kinase 1, mammalian rapamycin target, SHP2, androgen receptor, oxytocin receptor, microsome transfer protein inhibitor, 5-alpha reductase, angiotensin II, glycine receptor, noradrenaline reuptake receptor, estrogen receptor, estrogen-related receptor, localized adhesion kinase, Src, endothelin receptor, neuropeptide Y and receptor, adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase, TrkA The group is selected from the following: NGF receptor, beta-amyloid, tyrosine kinase Flk-1, vitronectin receptor, integrin receptor, Her-2 / neu, telomerase, cytosolic phospholipase A2 and EGF receptor tyrosine kinase, ecdysone 20-monooxygenase, ion channels of GABA-gate chloride channels, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium channel protein and chloride channel protein, acetyl-CoA carboxylase, adenyl succinate synthetase, protoporphyrinogen oxidase and enolpyruvir schimate-phosphate synthase.

[0162] In one embodiment, Q is a portion of an Hsp90 inhibitor, kinase inhibitor, phosphatase inhibitor, HDM2 / MDM2 inhibitor, human BET bromodomain inhibitor, HDAC inhibitor, human lysine methyltransferase inhibitor, RAF receptor inhibitor, FKBP inhibitor, angiogenesis inhibitor, aryl hydrocarbon receptor inhibitor, androgen receptor inhibitor, estrogen receptor inhibitor, thyroid hormone receptor inhibitor, HIV protease inhibitor, HIV integrase inhibitor, acyl protein thioesterase 1 inhibitor, or acyl protein thioesterase 2 inhibitor.

[0163] In one embodiment, Q is a portion of a TANK-binding kinase 1 (TBK1) inhibitor, estrogen receptor α (ERα) inhibitor, bromodomain-containing protein 4 (BRD4) inhibitor, androgen receptor (AR) inhibitor, platelet-derived growth factor receptor inhibitor, p38 MAPK inhibitor, Bcr-Abl tyrosine kinase inhibitor, Her2 inhibitor, EGFR inhibitor, MDM2 inhibitor, bromodomain-containing protein 2 (BRD2) inhibitor, HDAC inhibitor, DHFR inhibitor, or c-Myc inhibitor.

[0164] In one embodiment, Q is a portion selected from the group consisting of trimethoprim, vorinostat, tamoxifen, JQ1, nutrin 3, afatinib, chloroalkane, dasatinib, BIRB796, FK-506, simvastatin, rapamycin, and sorafenib.

[0165] In one embodiment, Q is a portion that binds to a target protein. Such a target protein may be degraded or sequestered by an E3 ubiquitin ligase, which is selected from cereblon (CRBN), damaged DNA-binding protein 1 (DDB1), Cullin-4A (CUL4A), Cullin1 regulator (ROC1), and von Hipperlindau (VHL).

[0166] In one embodiment, the E3 ubiquitin ligase is CRBN.

[0167] In one embodiment, the general formula (A) described herein k -L1 or (A) k Compounds containing -LQ can simultaneously bind to a target protein and an E3 ubiquitin ligase. In one embodiment, binding induces ubiquitination of the target protein by the E3 ubiquitin ligase. In another embodiment, binding induces degradation of the target protein by the proteasome. [Table 6] TIFF2026143564000226.tif230162TIFF2026143564000227.tif163162TIFF2026143564000228.tif194162TIFF2026143564000229.tif111162

[0168] Linker L can be covalently bonded to portion Q at any position permitted by valence. In one embodiment, linker L is as shown in the table below. [ka] It is covalently connected to the Q portion via the specific location shown. [Table 7] TIFF2026143564000232.tif228162TIFF2026143564000233.tif250162

[0169] In one embodiment, the present invention relates to formula (A) k -LQ or (A) k The present invention relates to a pharmaceutical composition comprising a compound of -L1 and pharmaceutically acceptable carriers, additives, and / or excipients.

[0170] In one embodiment, the present invention relates to a method for treating a disease in a subject, the method being formula (A) k -LQ or (A)k This involves administering an effective amount of the compound having -L1.

[0171] In one embodiment, the present invention relates to a method for treating a disease in which dysregulated protein activity is the cause of the disease, the method being formula (A) k -LQ or (A) k This involves administering an effective amount of the compound having -L1.

[0172] In one embodiment, cancer includes squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, uterine cancer, leukemia, lymphoma, Burkitt lymphoma, non-Hodgkin lymphoma, melanoma, myeloproliferative disorders, multiple myeloma, sarcoma, for example, Ewing's sarcoma. The group is selected from angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, schwannoma, testicular tumor, thyroid cancer, astrocytoma, Hodgkin's disease, Wilms' tumor, and teratoma.

[0173] In another embodiment, the present invention relates to a method for treating or preventing one or more autoimmune diseases or disorders, comprising administering a composition comprising a pharmaceutically effective amount of the compound described herein and a pharmaceutically acceptable carrier to a subject requiring it. In one embodiment, the autoimmune disease or disorder is selected from multiple sclerosis, diabetes mellitus, lupus, celiac disease, Crohn's disease, ulcerative colitis, Guillain-Barré syndrome, scleroderma, Goodpasture syndrome, Wegener's granulomatosis, autoimmune epilepsy, Rasmussen's encephalitis, primary cholangiosclerosis, sclerosing cholangitis, autoimmune hepatitis, Addison's disease, Hashimoto's thyroiditis, fibromyalgia, Meniere's syndrome; transplant rejection (e.g., prevention of allograft rejection); pernicious anemia; rheumatoid arthritis; systemic lupus erythematosus; dermatomyositis; Sjögren's syndrome; lupus erythematosus; multiple sclerosis; myasthenia gravis; Reiter's syndrome; Graves' disease; and other autoimmune diseases or disorders.

[0174] In one embodiment, the subject is a human being.

[0175] In another aspect, the present invention relates to the general formula (A) described herein. k -L1 or (A) k The present invention relates to a method for modulating cereblon, comprising administering a composition containing a compound having -LQ, or a salt, enantiomer, stereoisomer, polymorph, or its N-oxide, to a subject requiring it.

[0176] In another aspect, the present invention relates to the general formula (A) described herein. k -L1 or (A) k The present invention relates to a method for regulating protein sequestration to the proteasome, comprising administering a composition containing a compound having -LQ, or a salt, enantiomer, stereoisomer, polymorph, or its N-oxide, to a subject requiring it.

[0177] In another aspect, the present invention relates to the general formula (A) described herein. k -L1 or (A) kThe present invention relates to a method for regulating protein sequestration to the proteasome, comprising administering a composition containing a compound having -LQ, or a salt, enantiomer, stereoisomer, polymorph, or its N-oxide, to a subject requiring it.

[0178] Examples General synthesis scheme The compounds of the present invention can generally be prepared using synthetic techniques known to those skilled in the art, starting from commercially available starting materials. Several reaction schemes suitable for preparing the compounds of the present invention are outlined below. Further examples are provided in the specific examples.

[0179] Example 1: Competitive Assay CRBN binding is assessed using MAPPIT-like assays by determining the ability of test compounds to compete with trimethoprim-lenalidomide hybrid ligands for binding to intracellular CRBN. For example, the conventional MAPPIT assay described in Lemmens et al., "MAPPIT, a mammalian two-hybrid method for in-cell detection of protein-protein interactions," Methods Mol Biol. 2015;1278:447-55, is used to monitor protein-protein interactions. Bait protein (protein A) is expressed as a fusion protein fused to an engineered intracellular receptor domain of the leptin receptor, and the leptin receptor itself is fused to the extracellular domain of the erythropoietin (Epo) receptor. The Epo ligand binds to the EpoR component, activating receptor-associated intracellular JAK2. However, the activated JAK2 cannot activate the leptin receptor to cause STAT3 binding and its phosphorylation. This is because the tyrosine residue normally phosphorylated by activated JAK2 is mutated. Instead, the reconfiguration of the JAK2 phosphorylation-enabled STAT3 docking site is created by the interaction of protein B and protein A, thereby allowing protein B to fuse to the cytoplasmic domain of the gp130 receptor (where it possesses the appropriate tyrosine recognized by activated JAK2 kinase). Thus, the physical interaction between protein A and protein B is reconfigured, and Epo triggers activation of the JAK2-STAT3 signaling pathway. STAT3 activation can be monitored by introducing a STAT3-responsive reporter gene, such as a gene encoding luciferase or a gene encoding a fluorescent marker such as GFP or several other types of fluorescent proteins (e.g., EGF). Thus, the MAPPIT assay provides a versatile assay for evaluating such recombinant protein-protein interactions, or compound or hybrid ligand-induced protein-protein interactions, in intact cells.

[0180] Here, a similar MAPPIT-like assay is used to determine the ability of test compounds to compete with trimethoprim-lenalidomide-induced binding between DHFR and CRBN. Therefore, HEK293 cells transfected with appropriate cDNA encoding the transgene (encoding the DHFR and CRBN fusion proteins) are used to produce a positive assay signal as a result of ternary protein / compound complex formation, such as the formation of a DHFR-TMP-LEN-CRBN complex, which is formed by the trimethoprim (TMP)-lenalidomide hybrid ligand (TMP being the ligand for DHFR) and the CRBN-gp130 fusion protein (CRBN binding to the ligand lenalidomide). Complex formation leads to activation of a STAT-responsive luciferase reporter gene. The signal is set to 100% luciferase activity. In a different sample setup, cells are prepared in the same manner, but are also co-cultured with test compounds whose interaction with CRBN has been investigated. Binding to the CRBN fusion protein competes with the binding of the hybrid ligand to the same CRBN protein, thus inhibiting the assay signal by preventing the formation of the ternary complex required to generate the assay signal. The specificity of signal inhibition, which determines the CRBN binding efficiency determined in this type of ligand competition experiment in living cells by evaluating the increasing concentration of the test compound, is assessed by a parallel experimental setting that evaluates the effect of the test compound on inhibiting the signal generated by a control gp130 fusion protein (CTRL) that directly binds to the DHFR fusion protein (i.e., direct protein interaction) in the absence of the hybrid ligand.

[0181] More specifically, HEK293T cells were cultured in Dulbecco's Modified Eagle Medium supplemented with 10% fetal bovine serum at 37°C and 8% CO2. The cells were transfected with plasmids encoding *E. coli* dihydrofolate reductase (DHFR) fused to the tail of the cytoplasmic domain of the mutant leptin receptor (pCLG-eDHFR), plasmids encoding CRBN prey fused to the gp130 cytoplasmic domain (pMG1-CRBN), plasmids encoding REM2 control prey capable of directly interacting with the leptin receptor of the DHFR-fusion protein (pMG1-REM2), and STAT3-responsive pXP2d2-rPAPI-luciferase reporter plasmids. These were transfected using standard transfection methods as described (Lievens, et al. "Array MAPPIT: high-throughput interactome analysis in mammalian cells" Journal of Proteome Research 8.2(2009):877-886). Cells are treated with leptin to activate the leptin receptor fusion protein, and 24 hours after transfection, they are supplemented with 300 nM of the trimethoprim-lenalidomide fusion compound (a hybrid ligand in which trimethoprim interacts with DHFR and lenalidomide interacts with CRBN), with or without the indicated dose of the test compound. Luciferase activity induced by the formation of a ternary complex containing DHFR-trimethoprim-lenalidomide-CRBN and the resulting activation of STAT3 signaling is measured 24 hours after compound treatment using a luciferase assay system kit (PROMEGA, Madison, WI) equipped with an Ensight plate reader (PERKIN ELMER LIFE SCIENCES, Waltham, MA).The data points represent the mean luciferase activity of three samples, compared to leptin (CTRL) or leptin + hybrid ligand (CRBN) treated with the REM2 control (CTRL), for which the cells were treated with either leptin + test compound or leptin + hybrid ligand + test compound (CRBN). (In both cases, the signal obtained without the test compound is set to 100% of luciferase activity on the y-axis.) Error bars represent the standard deviation. The curves were fitted using 4-parameter nonlinear regression in GRAPHPAD PRISM software.

[0182] Example 2: Mobilization Assay: In this Example 2, a MAPPIT-like assay similar to that described in Example 1 is applied to determine the inducible binding of the test compound to the specific substrate protein of interest to CRBN. In this experimental setup, cells are transfected with a construct encoding a CRBN fusion protein and another construct encoding a substrate fusion protein. The activity of the test compound is evaluated by increasing the concentration of the test compound to monitor its ability to promote CRBN-ligand-induced protein interactions (dose-response study).

[0183] Specifically, HEK293T cells are transfected with a plasmid encoding MAPPIT receptor fusion (where the target protein (CRBN or substrate protein) is genetically linked to the cytoplasmic domain of the leptin receptor, which then fuses itself to the extracellular domain of the erythropoietin (Epo) receptor (pSEL-X (where X represents either CRBN or the target substrate protein)) or the extracellular domain of the leptin receptor (pCLG-X, where X represents either CRBN or the target substrate protein)), a plasmid encoding MAPPIT gp130 fusion (pMG1-Y (where Y is either the target substrate protein or CRBN)), and a reporter plasmid encoding STAT3-responsive luciferase (pXP2d2-rPAPI-luciferase reporter plasmid) (these are described in Lievens, et al. "Array MAPPIT: high-throughput interactome analysis in mammalian cells," Journal of Proteome Research). (As described in 8.2(2009):877-886). The full-size protein is fused to each of the target proteins tested, except for IKZF1, where isoform 7 is used, and BRD4, where isoform 3 is applied. The following construct combinations are used in this study: Recruitment of IKZF1: pSEL-CRBN+pMG1-IKZF1 (isoform 7); Recruitment of ASS1: pSEL-CRBN+pMG1-ASS1; Recruitment of SALL4: pSEL-SALL4 +pMG1-CRBN; DHFR mobilization: pCLG-DHFR+pMG1-CRBN; ESR1 mobilization: pSEL-CRBN+pMG1-ESR1; BRD4 mobilization: pSEL-CRBN+pMG1-BRD4 (isoform 3). Cells are treated 24 hours after transfection with or without the indicated doses of the test compound with erythropoietin (Epo; when the pSEL receptor fusion construct is used) or leptin (when the pCLG receptor fusion construct is applied).Luciferase activity is measured 24 hours after treatment with the test compound using a Luciferase Assay System kit (PROMEGA, Madison, WI) equipped with an Ensight plate reader (PERKIN ELMER LIFE SCIENCES, Waltham, MA). Data points show the induction factor of the mean luciferase activity from three samples: cells treated with Epo or leptin + test compound and cells treated with Epo or leptin alone. Error bars represent the standard deviation. Curves are fitted using 4-parameter nonlinear regression in GRAPHPAD PRISM software.

[0184] Example 3: Proteolytic Bioassay The following bioassays were performed using representative compounds disclosed herein to evaluate the levels of proteolysis observed in various cell types.

[0185] In each bioassay, cells were treated with varying amounts of the compounds contained herein. This study evaluated the degradation of the following proteins: TANK-binding kinase 1 (TBK1), estrogen receptor α (ERα), bromodomain-containing protein 4 (BRD4), androgen receptor (AR), and c-Myc.

[0186] 1. TBK1 Western Protocol Panc02.13 cells were purchased from ATCC and cultured in RPMI-1640 (Gibco) supplemented with 15% FBS (ATCC) and 10 units / mL of human recombinant insulin (Gibco). DMSO control and compound treatments (0.1 μM, 0.3 μM, and 1 μM) were performed in 12-well plates for 16 hours. The TLR3 agonist PolyI:C (Invivogen; tlrl-pic) was added during the last 3 hours. Cells were harvested and lysed in RIPA buffer (50 mM Tris pH 8, 150 mM NaCl, 1% Tx-100, 0.1% SDS, 0.5% sodium deoxycholate) supplemented with protease and phosphatase inhibitors. The lysates were clarified at 16,000 g for 10 minutes, and the supernatant was separated by SDS-PAGE. Immunoblotting was performed using a standard protocol. The antibodies used were TBK1 (Cell Signaling #3504), pIRF3 (abcam #ab76493), and GAPDH (Cell Signaling #5174). Bands were quantified using the Biorad ChemiDocMP imaging system.

[0187] 2. ERRα Western Protocol NAMALWA cells (ATCC) were cultured in RPMI-1640 (Life Technologies) supplemented with 15% FBS (Life Technologies). DMSO control and compound incubation (0.1 μM, 0.3 μM, and 1 μM) were performed in 24-well plates for 16 hours. Cells were harvested and lysed with cell lysis buffer (Cell Signaling Technologies) containing a protease inhibitor (Thermo Scientific). The lysates were clarified at 16,000 g for 10 minutes, and the supernatant was separated by SDS-PAGE. Immunoblotting was performed using a standard protocol. The antibodies used were ERRα (Cell Signaling #8644) and GAPDH (Cell Signaling #5174). Bands were quantified using the Bio-Rad ChemiDoc MP imaging system.

[0188] 3. BRD4 Western Protocol VCaP cells were purchased from ATCC and cultured in Dulbecco's Modified Eagle Medium (ATCC) supplemented with 10% FBS (ATCC) and penicillin / streptomycin (Life Technologies). DMSO control and compound treatments (0.003 μM, 0.01 μM, 0.03 μM, and 0.1 μM) were administered in 12-well plates for 16 hours. Cells were harvested and lysed in RIPA buffer (50 mM Tris pH 8, 150 mM NaCl, 1% Tx-100, 0.1% SDS, 0.5% sodium deoxycholate) supplemented with protease and phosphatase inhibitors. The lysates were clarified at 16,000 g for 10 minutes, and protein concentration was measured. Equivalent volumes of protein (20 μg) were subjected to SDS-PAGE analysis, followed by immunoblotting according to the standard protocol. The antibodies used were BRD4 (Cell Signaling #13440) and actin (Sigma #5441). The detection reagent was Clarity Western ECL substrate (Bio-rad #170-5060).

[0189] 4. AR ELISA protocol VCaP cells were purchased from ATCC and cultured in Dulbecco's Modified Eagle Medium (ATCC) supplemented with 10% FBS (ATCC) and penicillin / streptomycin (Life Technologies). DMSO control and compound treatment (0.0001 μM–1 μM) were performed in 96-well plates for 16 hours. Cells were harvested and lysed in cell lysis buffer (catalog #9803) (20 mM Tris-HCl (pH 7.5), 150 mM NaCl, 1 mM Na2EDTA, 1 mM EGTA, 1% Triton, 2.5 mM sodium pyrophosphate, 1 mM β-glycerophosphate, 1 mM Na3VO4, 1 μg / ml leupeptin). The lysate was clarified at 16,000 g for 10 minutes and PathScan AR was performed. The samples were loaded into an ELISA (Cell Signaling Catalog #12850). The PathScan® Total Androgen Receptor Sandwich ELISA Kit is a solid-phase sandwich enzyme-coupled immunosorbent assay (ELISA) for detecting endogenous levels of total androgen receptor protein. Microwells are coated with androgen receptor rabbit mAbs. After incubation with cell lysates, androgen receptor proteins are captured by the coated antibodies. After thorough washing, androgen receptor mouse detection mAbs are added to detect the captured androgen receptor proteins. Next, an anti-mouse IgG, HRP-conjugated antibody is used to recognize the conjugated detection antibody. TMB, an HRP substrate, is added to induce color development. The magnitude of the absorbance of the developed color is proportional to the total amount of androgen receptor protein.

[0190] 5. c-MycELISA assay protocol 22RV-1 cells were purchased from ATCC and cultured in RPMI+10% FBS medium. Cells were harvested and counted using trypsin (Gibco #25200-114) and seeded at 30,000 cells / well in RPMI+10% FBS medium at a volume of 75 μL / well in 96-well plates. Cells were administered a compound diluted with 0.1% DMSO, incubated for 18 hours, washed, and dissolved in 50 μL of RIPA buffer (50 mM Tris pH 8, 150 mM NaCl, 1% Tx-100, 0.1% SDS, 0.5% sodium deoxycholate) supplemented with protease and phosphatase inhibitors. The lysates were clarified at 4000 rpm, 4°C for 10 minutes, and aliquots were added to 96-well ELISA plates of the Novex Humanc-MycELISA kit, Life Technologies catalog #KH02041. 50 μl of c-Myc detection antibody was added to each well, and the plate was incubated at room temperature for 3 hours, then washed with ELISA wash buffer. 100 μl of anti-rabbit IgG-HRP secondary antibody was added to each well and incubated at room temperature for 30 minutes. The plate was washed with ELISA wash buffer, and 100 μl of TMB was added to each well, with the color change monitored every 5 minutes. 100 μl of stop solution was added, and the plate was read at 450 nm.

[0191] Example 4: Preparation of the compound The compounds of the present invention can be prepared by methods well known in the field of organic chemistry. For example, see J. March, "Advanced Organic Chemistry," 4th edition, John Wiley and Sons. During the synthetic sequence, it may be necessary and / or desirable to protect any sensitive or reactive groups on any of the molecules involved. This is achieved by conventional protecting groups, such as those described in TW Greene and PGMWutts, "Protective Groups in Organic Synthesis," 3rd edition, John Wiley and Sons, 1999. The protecting groups are optionally removed at an appropriate subsequent step using methods well known in the art. The reaction products are optionally isolated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, and chromatography, as needed. Such materials are optionally characterized using conventional means, such as physical constants and spectral data.

[0192] When synthesizing the compounds of the present invention, it may be desirable to use specific leaving groups. The term "leaving group" ("LG") generally refers to a group that can be substituted by a nucleophile. Such leaving groups are known in the art. Examples of leaving groups, but not limited to these, include halides (e.g., I, Br, F, Cl), sulfonates (e.g., mesylates, tosylates), sulfides (e.g., SCH3), N-hydroxysuccinimide, and N-hydroxybenzotriazole. Examples of nucleophiles, but not limited to these, include amines, thiols, alcohols, Grignard reagents, and anionic species (e.g., alkoxides, amides, carbanions).

[0193] HPLC purification Purification was performed using HPLC (H2O-MeOH; Agilent 1260 Infinity system with DAD and mass detector). The material was dissolved in 0.7 mL of DMSO using a Waters Sunfire C18 OBD preparative column (100 A, 5 μm, 19 mm x 100 mm, SunFire C18 Prep Guard Cartridge, 100 A, 10 μm, 19 mm x 10 mm). Flow rate: 30 mL / min. The purity of the obtained fractions was confirmed by analytical LC-MS. The spectra of each fraction were recorded immediately after chromatography in solution form. The solvent was evaporated at 80°C in an N2 flow. The fractions were unified based on LC-MS analysis after chromatography. The solids were dissolved in 0.5 mL of MeOH and transferred to pre-weighed marked vials. The resulting solutions were again evaporated at 80°C in an N2 flow. After drying, the product is finally analyzed by LC-MS and 1 The characteristics were evaluated by 1HNMR.

[0194] Analysis method NMR Equipment specifications: Bruker AVANCE DRX 500 Varian UNITYplus 400 LC / MS Equipment specifications: Agilent 1100 series LC / MSD system equipped with DAD\ELSD and Agilent LC\MSD VL (G1956A) and SL (G1956B) mass spectrometers. Agilent 1200 series LC / MSD system equipped with DAD\ELSD and Agilent LC\MSD SL (G6130A) and SL (G6140A) mass spectrometers. All LC / MS data were obtained using positive / negative mode switching. Zorbax SB-C18 1.8μm 4.6x15mm Rapid Resolution Column Cartridge (PN 821975-932) Mobile phase: A-acetonitrile, 0.1% formic acid B-Water (0.1% formic acid) Flow rate 3ml / min Gradient 0 min - 100% B 0.01 min-100%B 1.5 minutes-0%B 1.8 minutes-0%B 1.81 min-100%B Injection volume 1μl Ionization mode: Atmospheric pressure chemical ionization (APCI) Scan range m / z 80-1000

[0195] Example 5: Activity of an exemplary bifunctional compound

[0196] a. Synthesis of TMP-LEN TMP-LEN was prepared according to the following reaction scheme. [ka]

[0197] To a 100 mL benzene solution containing 4-pentic acid (51) (3.4 g, 34.5 mmol), oxalyl chloride (17.5 g, 138 mmol) was added, followed by 2 drops of DMF. The mixture was stirred at 80°C for 2 hours and evaporated to dryness to obtain chloroanhydride (52) (3.1 g, 76%), which was used in the next step without further purification.

[0198] To a 30 mL THF solution containing (50) (345 mg, 1.33 mmol), 5 mL of THF containing chloroanhydride (52) (315 mg, 2.70 mmol) was added, and the mixture was stirred at 75°C for 7 hours. The reaction mixture was quenched with 0.5 mL of MeOH, stirred for 1 hour, and evaporated to dryness. The solid residue was washed with Et2O and dried to obtain compound (53) (541 mg, 100%).

[0199] To a 10 mL DMF-H2O solution (2:1) containing compound (53) (33 mg, 0.112 mmol) and TMP-azide (63 mg, 0.109 mmol), sodium ascorbate (24 mg, 0.120 mmol) was added, followed by the addition of CuSO45H2O (27 mg, 0.109 mmol). The mixture was stirred at ambient temperature for 15 hours. The mixture was diluted with H2O, extracted with CHCl3, and the organic layer was discarded. The aqueous layer was evaporated to dryness, and the target product was purified by C18 reversed-phase HPLC column and eluted with a gradient MeCN-H2O-0.1% TFA. The fraction containing the target product was evaporated to dryness to obtain compound TMP-LEN (23 mg, 23%) as a solid.

[0200] b. Evaluation of inductive binding of lenalidomide hybrid ligands between CRBN and DHFR The binding between CRBN and DHFR (dihydrofolate reductase) induced by a hybrid molecule consisting of DHFR ligand trimethoprim (TMP) fused to CRBN ligand lenalidomide (LEN) via a PEG linker was evaluated using a MAPPIT-like assay similar to that described in Example 1. Similar to the protocol described in Example 1, HEK293T cells were co-transfected with a reporter plasmid encoding STAT3-responsive luciferase (pXP2d2-rPAPI-luciferase reporter plasmid) with a plasmid encoding a fusion construct of a (E. coli) DHFR anchor protein fused to a chimeric MAPPIT receptor containing a leptin receptor (pCLG-DHFR) and a leptin receptor extracellular domain linked to an engineered intracellular domain of a gp130-CRBN bait fusion construct. These findings are described in Lievens, et al. "Array MAPPIT: high-throughput interactome analysis in mammalian cells" (Journal of Proteome Research 8.2(2009):877-886). Twenty-four hours after transfection, cells were treated with leptin either without the TMP-LEN hybrid ligand or with the indicated concentrations of the TMP-LEN hybrid ligand. After a further 24 hours, luciferase activity was determined using a luciferase assay system kit (PROMEGA, Madison, WI) equipped with an Ensight plate reader (PERKIN ELMER LIFE SCIENCES, Waltham, MA). The dose-response curves shown in Figure 3 represent the induction ratio of mean luciferase activity for three samples of cells treated with leptin + test compound versus leptin alone. Error bars represent the standard deviation, and the curves were fitted using 4-parameter nonlinear regression in GRAPHPADPRISM software. This example demonstrates that the MAPPIT assay described herein can be applied to evaluate the binding between two proteins induced by a hybrid ligand.

[0201] Example 6: Test Results The following compounds were tested in the competitive and / or recruitment assays described herein, and the results are described below. Table 6: Competitive IC50 values ​​were determined using the protocol and reagents described in Example 1. EC50 values ​​for the mobilization of IKZF1, ASS1, and SALL4 were determined using the protocol and reagents described in Example 2. Mobilization evaluation was performed for each compound. TRUE = Mobilization of any tested substrate was observed at any test compound concentration from among IKZF1, ASS1, and SALL4. FALSE = Mobilization of any test substrate was not observed at any test compound concentration from among IKF1A, SS1, and SALL4. NA indicates that no substrate mobilization was observed at any test concentration. >> indicates that the EC50 curve could not be calculated because the value did not reach a plateau within the measured concentration range. << indicates that the EC50 curve could not be calculated because, at the initial concentration (13.7 nM) in which the compound was tested, the value exceeded 50% of the control at the time of reading. [Table 8] TIFF2026143564000236.tif242160TIFF2026143564000237.tif242160TIFF2026143564000238.tif242161TIFF2026143564000239.tif242161TIFF2026143564000240.tif242161TIFF2026143564000241.tif242162TIFF2026143564000242.tif242161TIFF2026143564000243.tif241162TIFF2026143564000244.tif242160TIFF2026143564000245.tif242161TIFF2026143564000246.tif242162TIFF2026143564000247.tif242162TIFF2026143564000248.tif242161TIFF2026143564000249.tif242161TIFF2026143564000250.tif242160TIFF2026143564000251.tif242161TIFF2026143564000252.tif242161TIFF2026143564000253.tif242161TIFF2026143564000254.tif242163TIFF2026143564000255.tif242162TIFF2026143564000256.tif242161TIFF2026143564000257.tif242160TIFF2026143564000258.tif242160TIFF2026143564000259.tif242161TIFF2026143564000260.tif242161TIFF2026143564000261.tif242161TIFF2026143564000262.tif242160TIFF2026143564000263.tif242161TIFF2026143564000264.tif242161TIFF2026143564000265.tif242160TIFF2026143564000266.tif242161TIFF2026143564000267.tif241161TIFF2026143564000268.tif241161TIFF2026143564000269.tif239162TIFF2026143564000270.tif240161TIFF2026143564000271.tif241161TIFF2026143564000272.tif240162TIFF2026143564000273.tif241160TIFF2026143564000274.tif242161TIFF2026143564000275.tif241161TIFF2026143564000276.tif240160TIFF2026143564000277.tif241161TIFF2026143564000278.tif242161TIFF2026143564000279.tif241161TIFF2026143564000280.tif242162TIFF2026143564000281.tif242161TIFF2026143564000282.tif240162TIFF2026143564000283.tif241161TIFF2026143564000284.tif241160TIFF2026143564000285.tif242160TIFF2026143564000286.tif238160TIFF2026143564000287.tif240162TIFF2026143564000288.tif242162TIFF2026143564000289.tif241162TIFF2026143564000290.tif241161TIFF2026143564000291.tif240162TIFF2026143564000292.tif241161TIFF2026143564000293.tif240160TIFF2026143564000294.tif241160TIFF2026143564000295.tif240160TIFF2026143564000296.tif240161TIFF2026143564000297.tif241160TIFF2026143564000298.tif241162TIFF2026143564000299.tif240162TIFF2026143564000300.tif241160TIFF2026143564000301.tif241161TIFF2026143564000302.tif241160TIFF2026143564000303.tif238 161TIFF2026143564000304.tif242162TIFF2026143564000305.tif238161TIF F2026143564000306.tif239160TIFF2026143564000307.tif253169TIFF20261 43564000308.tif240160TIFF2026143564000309.tif240162TIFF202614356400 Table 7: Competitive IC50 values ​​were determined using the protocol and reagents described in Example 1. The EC50 values ​​for the recruitment of the indicated target proteins were determined using the protocol and reagents described in Example 2. NA indicates that no substrate recruitment was observed at any test concentration. >> indicates that an EC50 curve could not be calculated because the value did not reach a plateau within the measured concentration range. << indicates that an EC50 curve could not be calculated because, at the initial concentration (13.7 nM) tested for the compound, the value exceeded 50% of the control at the time of reading. [Table 9]

[0202] Example 7: Evaluation of CRBN binding and / or substrate mobilization of a bifunctional compound For the selected bifunctional compounds, the competitive assay and / or recruitment assay described in Example 1 and Example 2 were applied, respectively, to evaluate CRBN binding and / or substrate recruitment. The resulting dose-response curves are shown in Figure 3.

[0203] Example 8: Synthetic intermediate and final compound Intermediate synthesis Synthesis of Intermediate 1: [ka]

[0204] To a 50 mL solution of DCM containing SM1 (5.0 g, 13.5 mmol) at 0°C under an N2 atmosphere, SM2 (3.8 g, 27.0 mmol) was added, and the mixture was then heated overnight at 60°C.

[0205] The reaction mixture was cooled to room temperature, concentrated, and the residue was dissolved in MeOH (50 mL). The mixture was heated under reflux for 3 hours, then concentrated to obtain target 1.1 (4.5 g, yield 94%) as a white solid. TLC:R f =0.15(DMC / MeOH=10:1, v / v, 254nm). LCMS:(Method P0-POS):m / z358.2[M+H] + , 2.109 minutes.

[0206] To a 50 mL solution of DCM containing compound 1.1 (4.5 g, 12.6 mmol), SM3 (2.9 g, 15.1 mmol) and DIPEA (4.9 g, 37.8 mmol) were added, and the resulting mixture was stirred overnight at room temperature.

[0207] The mixture was diluted with water (100 mL) and extracted with DCM (50 mL x 3). The combined organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column (eluent petroleum DCM:MeOH = 40:1, v:v) to obtain product 1.2 (4.9 g, yield 83%) as a white solid.

[0208] To a 1-4 dioxane (20 mL) solution containing compound 1.2 (4.9 g, 10.4 mmol), 4N HCl / dioxane (30 mL) was added, and the mixture was stirred at room temperature for 4 hours.

[0209] The mixture was concentrated, and the residue was ground with ether to obtain intermediate 1 (4g, 93%) as a white solid. TLC:R f 0.1(DCM / MeOH=10:1,v / v,254nm)LCMS:(P0(-1)-POS):m / z416.2[M+H]+,3.457min.1HNMR( 400MHz,DMSO-d6)(FIDNo:CJP-0147-084-HNMR)δ7.40-7.37(m,2H),7.31-7.27(m,1H),7.2 2-7.19(m,4H),7.14-7.11(m,3H),6.79-6.77(m,2H),6.66-6.64(m,2H),4.25(t,J=4.4Hz, 2H),4.13(s,2H),3.54-3.53(m,2H),2.89(s,3H),2.40-2.34(m,2H),0.85(t,J=7.2Hz,3H)

[0210] Synthesis of Intermediate 2 [ka]

[0211] To a pyridine (300 mL) solution containing acid (21 g, 111.57 mmol) and amine (20.53 g, 111.57 mmol), POCl3 (13.07 g, 133.89 mmol) was added at 0°C, and the mixture was stirred at room temperature for 30 minutes.

[0212] The mixture was diluted with water (600 mL) and extracted with SiO2 (200 mL x 3). The combined organic layer was washed with brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:SiO2, 1:1, v / v) to obtain 2.1 (10 g, 31%) as a yellow solid. TLC:R f=0.49 (petroleum ether:EtOAc=1:1, v / v, 254nm). LCMS: (LCMS method P2-POS): m / z288.20[M+H] + , 3.598 minutes.

[0213] To a 100 mL solution of MeOH containing NH2OH·HCl (11.49 g, 348 mmol), KOH (29.29 g, 522 mmol) was added at 0°C, and the mixture was stirred for 1 hour. The resulting precipitate was filtered off, and the solution of free NH2OH was placed in a round-bottom flask and cooled in an ice bath. Compound 2.1 (10 g, 34.8 mmol) was added to the solution, and the mixture was stirred overnight at room temperature.

[0214] The mixture was diluted with water (200 mL), acidified with AcOH to a pH of approximately 5, and then kept in a refrigerator at +4°C for 3 hours. The precipitate was collected by filtration, washed with water, and crystallized from acetone / THF (1:1, v / v) to obtain intermediate 2 (7 g, 70%) as a white solid. TLC:R f =0(EtOAc / petroleum ether=1 / 1, v / v). LCMS:(Method P2-POS):m / z289.20[M+H] + 2.820 min. 1 1H NMR: 1 H NMR (400 MHz, DMSO-d6) (FID No:YJ-0489-075-HNMR) 10.32(s, 1H), 10.03(s, 1H), 8.65(s, 1H), 7.61-7.59 (m, 2H), 7.40-7.38 (m, 2H), 4.06 (s, 1H), 2.32-2.28 (m, 2H), 1.95-1.91 (m, 2H), 1.58-1.47 (m, 4H), 1.28-1.27 (m, 4H).

[0215] Synthesis of Intermediate 3 [ka] To a 15 mL solution of DCM containing SM (2.4 g, 5.25 mmol), TFA (10 mL) was added, and the mixture was stirred overnight at room temperature. TLC showed that the SM was consumed. The solvent was removed by vacuum. The residue was pulverized with water (25 mL x 2) to obtain intermediate 3 (2.00 g, 95%) as a pale yellow solid. LCMS: (Method P2-POS): m / z 401.10 [M+H] + ,3.209 minutes, 1 H NMR: (400MHz, DMSO-d6, FID number: WFL-0259-100-1-20190227-HNMR)δ12.43(s,1H),7.50(d,J=8.8Hz,2H),7.47-7.41(m,2H) ,4.45(t,J=7.2Hz,1H),3.43(dd,J=16.8,6.8Hz,1H),3.32(dd,J=16.8,7.4Hz,1H),2.60(s,3H),2.41(s,3H),1.63(s,3H).

[0216] Synthesis of Intermediate 9 [ka] At 0°C, SOCl2 (59g, 0.5mol) was added to a MeOH (300mL) solution containing SM1 (46g, 0.3mol), and the mixture was heated at 70°C for 2 hours. The mixture was then concentrated to obtain product 9.1 (42g, 84%) as a brown solid. TLC:R f =0.65(DCM:MeOH=20:1, v / v, 254nm). 1 1H NMR: 1 H NMR (400 MHz, DMSO-d6) (FID No:CJP-0147-055-HNMR)δ9.69(m, 1H), 7.18-7.16(m, 1H), 7.07(t, J=8Hz, 1H), 7.00-6.98(m, 1H), 3.79(s, 3H), 2.27(s, 3H)

[0217] To a 500 mL solution of DCM containing 9.1 (65 g, 0.39 mol), imidazole (91.4 g, 1.17 mol) and TBSCl (70.5 g, 0.47 mol) were added, and the mixture was stirred at room temperature for 2 hours.

[0218] The mixture was diluted with water (800 mL) and extracted with dimethyl (300 mL x 3). The combined organic layer was washed with brine (400 mL), dried over Na2SO4, filtered, and concentrated to obtain product 9.2 (100 g, 91%) as a brown oil. TLC:R f =0.8(DMC:MeOH=20:1, v / v, 254nm). 1 1H NMR: 1 HNMR(400MHz,DMSO-d6)(FIDNo:FGX41-013-HNMR)δ7.35-7.33(m,1H),7.18(t,J= 8.4Hz,1H),7.04-7.01(m,1H),3.80(s,3H),2.31(s,3H),0.98(s,9H),0.21(s,6H)

[0219] To a CCl4 (500 mL) solution containing compound 9.2 (100 g, 0.36 mol), NBS (71.2 g, 0.40 mol) and AIBN (5.9 g, 0.036 mol) were added, and the mixture was heated under reflux for 3 hours.

[0220] The mixture was concentrated, the residue was diluted with water (500 mL), and extracted with DCM (200 mL x 3). The combined organic layer was washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated to obtain product 9.3 (120 g, 94%) as a brown oil. TLC:R f =0.3(DCM:MeOH=40:1,v / v,254nm) 1 H NMR:1H NMR(400 MHz,DMSO-d6)(FID No:FGX41-025-HNMR)δ7.47-7.45(m,1H),7.37(t,J=8 Hz,1H),7.16-7.14(m,1H),4.95(s,2H),3.86(s,3H),1.03(s,9H),0.29(s,6H)

[0221] To a 600 mL solution of ACN containing compound 9.3 (90 g, 0.25 mol), SM2 (45.1 g, 0.28 mol) and DIPEA (96.9 g, 0.75 mol) were added, and the mixture was heated overnight at 40°C.

[0222] The mixture was concentrated, and the residue was pulverized with dimethyl (150 mL x 2) to obtain compound 9.4 (60 g, 63%) as a white solid. TLC:R f =0.28(DCM:MeOH=10:1,v / v,254nm). LCMS: (LCMS method P2-POS): m / z375.1[M+H] + , 2.117 minutes.

[0223] To a THF (400 mL) solution containing compound 9.4 (50 g, 0.13 mol), TBAF (1 MTHF solution, 160 mL, 0.16 mol) was added, and the mixture was stirred at room temperature for 3 hours.

[0224] The mixture was concentrated under reduced pressure, and the residue was ground with ₹ (150 mL x 2) to obtain product 9.5 (28 g, 80%) as a white solid. TLC:R f =0.5(DCM:MeOH=10:1,v / v,254nm). LCMS: (LCMS method P2-POS): m / z261.0[M+H]+,1.611 min.

[0225] To a 100 mL solution of DMF containing compound 9.5 (16.0 g, 61.5 mmol), SM3 (8.4 g, 43.1 mmol), Na2CO3 (13.0 g, 123 mmol), and KI (2.0 g, 12.3 mmol) were added, and the mixture was heated at 60°C for 6 hours.

[0226] The mixture was diluted with water (800 mL), extracted with ethyl acetate (200 mL x 3), washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 200:1~40:1, v / v) to obtain product 9.6 (6.0 g, 26%) as a white solid. TLC:R f =0.6(DCM:MeOH=10:1,v / v,254nm). LCMS: (LCMS method S12): m / z 373.1[MH]-, 3.779 minutes.

[0227] At 0°C, TFA (40 mL) was added to a DCM (100 mL) solution containing compound 9.6 (14 g, 37.4 mmol), and the mixture was stirred at room temperature for 6 hours.

[0228] The mixture was concentrated, and the residue was rinsed with ether (100 mL) to obtain intermediate 9 (11 g, 92%) as a white solid. TLC:R f =0.2(DCM:MeOH=10:1,v / v,254nm). LCMS: (LCMS method P1-POS): m / z 319.1[M+H] + ,1.774 minutes 1 1H NMR: 1 HNMR(400MHz,DMSO-d6)(FIDNo:CJP-0147-102)δ10.97(s,1H),7.46(t,J=8Hz,1H),7.34-7.32(m,1H),7.17-7.15(m,1H),5. 13-5.08(m,1H),4.84(s,2H),4.42-4.24(m,2H),2.91-2.86(m,1H),2.61-2.56(m,1H),2.49-2.40(m,1H),2.02-1.98(m,2H).

[0229] Synthesis of intermediates 10-13 [ka] To a DMF (0.25 M) solution containing intermediate 9, HATU (2.0 equivalents) and DIPEA (3.0 equivalents) were added, and the mixture was stirred at room temperature for 30 minutes. Next, aminoazide (1.2 equivalents) was added, and stirring was continued at room temperature for 16 hours. The mixture was diluted with water, extracted with DCM / MeOH (15 / 1), the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by Biotage C18 column or p-TLC to obtain intermediates 10-13.

[0230] Intermediate 10 was purified using a Biotage C18 column (40% ACN / water) to obtain intermediate 10 (yield: 43%) as a colorless oil. LCMS: (Method S12): m / z 563.3 [M+H] + ,1.233 minutes,1 H NMR:(400 MHz, DMSO-d6, FID No:CJP-0147-104-HNMR)δ11.00(s,1H),8.11(t,J=5.6Hz,1H),7.47(t,J=8.0Hz,1 H),7.34(d,J=6.4Hz1H),7.13(d,J=8.0Hz1H),5.16-5.11(m,1H),4.64(s,2H),4.48 -4.32(m,2H),3.60-3.58(m,2H),3.50-3.48(m,4H),3.43-3.38(m,8H),3.39-3.28 (m,6H),2.97-2.90(m,1H),2.63-2.61(m,1H),2.44-2.37(m,1H),2.04-2.00(m,1H)

[0231] Intermediate 11 was purified using a Biotage C18 column (40% ACN / water) to obtain Int11 (yield: 25%) as a semi-solid. LC-MS (LC-MS method S12): m / z 519.3 [M+H] + ,2.333 minutes, 1 1H NMR: (400 MHz, DMSO-d6, FID) No:CJP-0147-099-HNMR)δ11.00(s,1H),8.11(t,J=5.6Hz,1H),7.47(t,J=8.0 Hz,1H),7.34(d,J=6.4Hz1H),7.13(d,J=8.0Hz1H),5.16-5.11(m,1H),4.64(s, 2H),4.48-4.32(m,2H),3.59-3.57(m,2H),3.50-3.44(m,8H),3.38-3.31(m,6 H),2.96-2.90(m,1H),2.62-2.59(m,1H),2.43-2.36(m,1H),2.03-1.99(m,1H)

[0232] Intermediate 12 was purified by preparative TLC (DCM:MeOH = 10:1, v / v) to obtain intermediate 12 as a yellow oil (yield: 63%). TLC:R f =0.18(DCM:MeOH=20:1,v / v,254nm)LCMS:(LCMS method P2):m / z=475.30[M+H]+,2.516min, 1 1H NMR: 11HNMR (400MHz, chloroform-d) (FIDNO:ZJ-0523-016-1HNMR) δ 8.14 (s, 1H), 7.57 (d, J=7.6Hz, 1H), 7.47 (t, J=7.8Hz, 1H), 7.02 (d, J=8.2Hz, 1H), 6.85 (s, 1H), 5.23 (dd, J=13.4, 5.2Hz, 1H), 4.61 (s, 2H), 4.52 (d, J=16.4Hz, 1H), 4.38 ( d,J=16.6Hz,1H),3.64-3.61(m,2H),3.60-3.55(m,6H),3.33(dd,J=5.6,4.4Hz,2H),3.03-2.89(m,1H),2.84(dd d,J=17.8,13.0,5.2Hz,1H),2.40(qd,J=13.0,5.0Hz,1H),2.24(ddd,J=10.2,5.2,2.8Hz,1H),1.58-1.36(m,2H)

[0233] Intermediate 13 was purified using a Biotage C18 column (40% ACN / water) to obtain Int-13 (yield: 27%) as a white solid. LC-MS (LC-MS method P0-POS): m / z 387.1[M+H]+, 2.165 min 1 HNMR:1HNMR(400MHz,DMSO-d6,FID No:LL-0450-112-HNMR)δ11.00(s,1H),8.30(t,J=5.4Hz,1H),7.47(t,J=7.8Hz,1H) ,7.35(d,J=7.2Hz,1H),7.15(d,J=7.8Hz,1H),5.14(dd,J=13.4,5.1Hz,1H),4.66(d, J=2.2Hz,2H),4.46(d,J=17.4Hz,1H),4.35(d,J=17.4Hz,1H),3.43-3.37(m,2H),3. 37-3.33(m,2H),2.99-2.86(m,1H),2.61(d,J=16.8Hz,1H),2.41(m,1H),2.02(m,1H)

[0234] Synthesis of compounds 5.49-5.52 listed in Table 5 General procedure To a tert-butanol / H2O (1 / 1, v / v) (0.03 M) solution containing azide (1.0 equivalent), intermediate 2 (1.0 equivalent), then CuSO4·5H2O (0.2 equivalents) and sodium ascorbate (1.0 equivalent) were added, and the mixture was heated at 80°C for 5 hours under an N2 atmosphere. The mixture was diluted with water, extracted with DCM / MeOH (15 / 1), washed with brine, dried over Na2SO4, filtered, concentrated, and purified by preparative TLC or preparative HPLC to obtain compounds 5.49–5.52.

[0235] Compound 5.49 was purified by preparative HPLC (water containing 5-60% ACN / 0.1% TFA) to obtain compound 5.49 (yield 5%) as a white solid. LC-MS (LC-MS method S12-5MIN): m / z 851.5[M+H]+, 1.047 min 1 H NMR:(400MHz,DMSO-d6)(FIDNo:CJP-0147-115-HNMR)δ11.00(s,1H),10.32(s,1H),9.94(s,1H),8.42(s,1H),8.11(t,J=6.0Hz,1 H),7.76-7.50(m,4H),7.46(t,J=8.0Hz,1H),7.35-7.33(m,1H),7.14-1.12(m,1H),5.16-5.11(m,1H),4.64(s,2H),4.54(t,J=5.2 Hz,2H),4.47-4.31(m,2H),3.84(t,J=5.2Hz,2H),3.53-3.47(m,3H),3.46-3.44(m,3H),3.44-3.41(m,8H),3.40-3.26(m,3H),2.9 5-2.89(m,1H),2.63-2.58(m,1H),2.443-2.40(m,1H),2.33-2.28(m,2H),2.02-1.94(m,3H),1.59-1.51(m,4H),1.49-1.21(m,4H)

[0236] Compound 5.50 was purified by preparative HPLC (5-60% ACN in water containing 0.1% TFA) to obtain compound 5.50 (yield 8%) as a colorless oil. LC-MS (LC-MS method S12-5MIN): m / z 807.4[M+H]+, 2.165 min 1H NMR: (400MHz, DMSO-d6) (FIDNo: CJP-0147-116-HNMR) δ11.00(s,1H),10.33(s,1H),9.95(s,1H),8.64(s,1H),8.42(s,1H),8.10(t,J=5. 6Hz,1H),7.75-7.65(m,4H),7.46(t,J=4.8Hz,1H),7.35-7.33(m,1H),7.14-1.11(m,1H),5.15-5.10(m,1H),4.63(s,2H),4.54(t,J=5.2 Hz,2H),4.46-4.30(m,2H),3.84(t,J=5.2Hz,2H),3.84-3.44(m,2H),3.42-3.40(m,2H),3.40(s,4H),3.33-3.28(m,2H),3.25-3.16(m,2 H),2.95-2.92(m,1H),2.86-2.58(m,1H),2.50-2.42(m,1H),2.39-2.30(m,2H),2.00-1.94(m,3H),1.59-1.49(m,5H),1.39-1.21(m,2H)

[0237] Compound 5.51 was fractionated and purified by TLC (DCM / MeOH=10 / 1, v / v), and compound 5.51 (yield: 12%) was obtained as a yellow solid. TLC:R f =0.29 (Petroleum alloy:EtOAc=5:1, v / v, 254nm). LCMS: (LCMS method P2): m / z 763.45 [M+H] + 2.421 points 1 H NMR: 1HNMR(400MHz,DMSO-d6)(FIDNO:ZJ-0523-018-HNMR)δ11.00(s,1H),10.33(s,1H),9.95(s,1H),8.65(s,1H),8.42(s,1H),8.09(s,1H), 7.73(s,2H),7.66(s,2H),7.44(d,J=7.9Hz,1H),7.34(d,J=7.6Hz,1H),7.12(d,J=8.2Hz,1H),4.58(d,J=37.0Hz,4H),4.41(s,1H),4.3 4(s,1H),3.84(d,J=6.6Hz,2H),3.55-3.45(m,4H),3.40(d,J=6.0Hz,2H),3.25(d,J=5.6Hz,2H),3.17(d,J=5.0Hz,2H),2.60(d,J=17.2 Hz,1H),2.40(d,J=12.6Hz,1H),2.30(t,J=7.6Hz,2H),1.94(t,J=7.4Hz,3H),1.53(d,J=35.6Hz,4H),1.28(s,4H),1.09(t,J=7.0Hz,1H)

[0238] Compound 5.52 was purified by preparative HPLC (5-60% ACN in water containing 0.1% TFA) to obtain compound 5.52 (yield: 34%) as a brown solid. LC-MS (LC-MS method S12): m / z 675.3 [M+H] + ,2.170 minutes, 1H NMR:(400MHz,DMSO-d6,FID No:LL-0450-115-HNMR)δ10.99(s,1H),10.32(s,1H),9.94(s,1H),8.42(s,1H),8.30(s,1H),7.72(s,2H),7.67(s,2H), 7.43(t,J=7.8Hz,1H),7.33(s,1H),7.10(d,J=7.8Hz,1H),5.11(dd,J=13.2,5.2Hz,1H),4.64(d,J=2.2Hz,2H),4.51(s, 2H),4.39(s,1H),4.34(s,1H),3.66-3.58(m,2H),2.91(ddd,J=17.4,13.6,5.2Hz,1H),2.58(d,J=17.2Hz,1H),2.40(td ,J=13.0,4.4Hz,1H),2.31(s,2H),2.07(s,4H),1.94(s,3H),1.58(d,J=7.2Hz,2H),1.54-1.45(m,2H),1.35-1.23(m,4H)

[0239] Synthesis of compounds 5.53 and 5.56 listed in Table 5 To a solution of THF (0.08 M) containing azide (1.0 equivalent), PPh3 (2.0 equivalents) and 2 M HCl (4.0 equivalents) were added, and the mixture was stirred overnight at room temperature. Another PPh3 (1.0 equivalent) was added, and stirring was continued for a further 8 hours. The solvent was removed by vacuum, and the residue was ground with diethyl ether to obtain the title amine intermediate, which was used directly in the next step without any further purification.

[0240] To a DMF (0.045 M) solution containing intermediate 1, amine intermediate (1.2 equivalents), then TBTU (1.5 equivalents) and DIPEA (3.0 equivalents) were added, and the mixture was stirred at room temperature under an N2 atmosphere for 16 hours. The mixture was diluted with water, extracted with DCM / MeOH (15 / 1), the combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC or preparative HPLC to obtain compounds 5.53 and 5.56.

[0241] Compound 5.53 was purified by preparative HPLC (water containing 5-80% ACN / 0.1% TFA) to obtain compound 5.53 (yield 6%) as a white solid. LC-MS (LC-MS method S12-5MIN): m / z 934.4 [M+H] + ,2.356 minutes 1 H NMR:(400MHz,DMSO-d6)(FIDNo:CJP-0147-132-HNMR)δ8(t,J=5.2Hz,1H).12,7.73-7.62(m,2H),7.46(t,J=8.0Hz,1H),7.39 -7.33(m,3H),7.29-7.26(m,1H),7.21-7.11(m,8H),6.74-6.59(m,4H),5.15-5.12(m,1H),4.64(s,2H),4.48-4.34(m,4H),4. 22(t,J=5.6Hz,1H),3,91(t,J=5.2Hz,1H),3.43-3.32(m,14H),3.19-3.18(m,2H),2.97-2.90(m,3H),2.68-2.58(m,3H),2.3 9-2.37(m,3H),2.25(s,3H),2.02-1.99(m,1H),1.66-1.62(m,1H),1.40-1.32(m,1H),0.91(t,J=7.6Hz,1H),0.86-080(m,3H)

[0242] Compound 5.56 was purified by preparative HPLC (5-80% ACN in water containing 0.1% TFA) to obtain compound 5.56 (yield: 10%) as a white solid. LC-MS (LC-MS method S12): m / z 758.3 [M+H] + ,3.088 minutes, 1H NMR:(400MHz,DMSO-d6,FID No:LL-0450-120-HNMR)δ9.80(s,1H),8.59(s,1H),8.15(d,J=5.8Hz,1H),7.63(s,1H),7.44(t,J=7.8Hz,1H),7.38(dd,J= 8.0,6.8Hz,2H),7.34-7.26(m,2H),7.22-7.17(m,4H),7.15-7.09(m,4H),6.77(d,J=8.8Hz,2H),6.64(d,J=8.8Hz,2H),4. 77(dd,J=10.2,4.7Hz,1H),4.62(d,J=17.6Hz,3H),4.43(d,J=18.0Hz,2H),4.18(s,2H),3.92(d,J=33.0Hz,3H),3.21(d,J =19.4Hz,4H),2.85(s,3H),2.37(d,J=7.4Hz,2H),2.26(s,2H),2.23-2.18(m,1H),2.10-2.00(m,1H),0.84(t,J=7.4Hz,3H)

[0243] Synthesis of compounds 5.54 and 5.55 listed in Table 5 To a 0.47 M DCM solution containing bisamine (1.0 equivalent), (Boc)2O (1.0 equivalent) and TEA (2.5 equivalents) were added, and the mixture was stirred at room temperature for 2 hours. The solvent was removed by vacuum, the residue was diluted with water, and extracted with SiO2. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to obtain mono-boc-amine, which was used directly in the next step without further purification.

[0244] To a solution of DMF (0.15 M) containing acid intermediates 1, 4, or 9 (1.0 equivalent), mono-boc-amine (1.2 equivalents), followed by TBTU (1.5 equivalents) and DIPEA (3.0 equivalents) were added, and the mixture was stirred at room temperature under an N2 atmosphere for 16 hours. The mixture was diluted with water and extracted with DCM / MeOH (30 / 1). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and the residue was purified by silica gel column chromatography to obtain the boc-protected intermediates.

[0245] Dioxane containing 4M HCl (8 equivalents) was added to a dioxane solution containing a BOC-protected intermediate, and the mixture was stirred at room temperature for 2-4 hours. The solvent was removed by vacuum to obtain the HCl salt described in the title, which was used directly in the next step.

[0246] To a DMF (0.045 M) solution containing intermediate 1 (1.0 equivalent), amine HCl salt (1.2 equivalents), followed by TBTU (1.5 equivalents) and DIPEA (3.0 equivalents) were added, and the mixture was stirred at room temperature under an N2 atmosphere for 16 hours. The mixture was diluted with water and extracted with DCM / MeOH (15 / 1). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and the residue was purified by preparative TLC or preparative HPLC to obtain the final compound.

[0247] Compound 5.54 was purified by preparative TLC (DCM / MeOH = 10 / 1, v / v) to obtain compound 5.54 (yield: 13%) as a pale white solid. TLC:R f =0.15(DCM:MeOH=10:1,v / v,254nm)LCMS:(LCMS method P2):m / z846.50[M+H]+,0.490min. 1 HNMR(400MHz,DMSO-d6)(FIDNO:ZJ-0523-039-HNMR)δ11.00(s,1H),8.11(t,J=5.8Hz,1H),7.69(s,1H),7.46(t,J=7.8Hz,1H),7.35 (t,J=8.0Hz,3H),7.30-7.25(m,1H),7.22-7.17(m,4H),7.14-7.10(m,4H),5.13(dd,J=13.2,5.2Hz,1H),4.63(d,J=1.6Hz,2H),4.4 4(d,J=17.6Hz,1H),4.33(d,J=17.6Hz,1H),3.93(t,J=5.6Hz,2H),3.43(s,3H),3.41-3.34(m,4H),3.27(q,J=6.2Hz,3H),3.18(d,J =5.8Hz,2H),3.02(s,2H),2.72(s,2H),2.44-2.32(m,4H),2.29(s,1H),2.03-1.97(m,1H),1.24(d,J=2.8Hz,3H),0.86-0.84(m,3H)

[0248] Compound 5.55 was purified by preparative TLC (DCM / MeOH = 10 / 1, v / v) to obtain compound 5.55 (yield: 11%) as a pale white solid. LCMS (LCMS method P2): m / z 890.4 [M+H] + 3.172 min. 1 HNMR(400MHz,DMSO-d6)(FIDNO:CJP-0147-137-HNMR)δ11.00(s,1H),8.12(t,J=5.6Hz,1H),7.68(s,1H),7.46(t,J= 7.6Hz,1H),7.39-7.28(m,4H),7.21-7.11(m,8H),6.74-6.59(m,4H),5.16-5.11(m,1H),4.64(s,2H),4.72-4.31(m,2 H),3.92(t,J=5.6Hz,2H),3.46-3.41(m,10H),3.36-3.32(m,2H),3.29-3.26(m,2H),3.19-3.16(m,2H),2.99-2.88(m ,3H),2.70-2.58(m,3H),2.39-2.34(m,2H),2.27(s,3H),2.02-1.98(m,1H),1.26-1.24(m,1H),0.84(t,J=7.2Hz,3H)

[0249] Synthesis of compounds 5.57-5.60 listed in Table 5 To a DMF (0.05 M) solution containing intermediate 3 (1.0 equivalent), amine HCl salt (1.2 equivalents), followed by TBTU (1.5 equivalents) and DIPEA (3.0 equivalents) were added, and the mixture was stirred at room temperature under an N2 atmosphere for 16 hours. The mixture was diluted with water and extracted with DCM / MeOH (15 / 1). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and the residue was purified by preparative TLC or preparative HPLC to obtain compounds 5.57–5.60.

[0250] Compound 5.57 was purified by preparative TLC (DCM / MeOH = 8 / 1, v / v) to obtain compound 5.57 (yield 4%) as a yellow solid. LC-MS (LC-MS method S12-5MIN): m / z 919.5 [M+H] + , 3.033 minutes. 1H NMR:(400MHz,DMSO-d6)(FIDNo:CJP-0147-135-HNMR)δ11.00(s,1H),8.27(t,J=5.6Hz,1H),8.12(t,J =5.6Hz,1H),7.49-7.47(m,3H),7.43-7.35(m,2H),7.35-7.33(m,1H),7.13(d,J=8Hz,1H),5.14-5.11( m,1H),4.64(s,2H),4.52-4.48(m,1H),4.43-4.30(m,2H),3.52-3.43(m,13H),3.33-3.25(m,4H),3.22 -3.21(m,5H),2.92-2.82(m,1H),2.62-2.59(m,4H),2.50-2.40(m,4H),2.03-1.99(m,1H),1.62(s,3H)

[0251] Compound 5.58 was purified by preparative TLC (DCM / MeOH = 10 / 1, v / v) to obtain compound 5.58 (yield 4%) as a white solid. LC-MS (LC-MS method S12-5MIN): m / z 875.2[M+H]+, 2.898 min 1 H NMR:(400MHz,DMSO-d6)(FIDNo:CJP-0147-138-HNMR)δ11.00(s,1H),8.27(t,J=5.6Hz,1H),8.13(t ,J=5.6Hz,1H),7.49-7.43(m,5H),7.40(d,J=7.6Hz,1H),7.13(d,J=8.0Hz,1H),5.14-5.11(m,1H),4 .64(s,2H),4.52-4.47(m,2H),4.43-4.31(m,1H),3.51(d,J=9.2Hz,8H),3.46-3.43(m,4H),3.32-3 .21(m,6H),2.96-2.88(m,1H),2.62-2.59(m,4H),2.50-2.40(m,4H),2.02-1.99(m,1H),1.62(s,3H)

[0252] Compound 5.59 was purified by preparative HPLC (water containing 5-50% ACN / 0.1% TFA) to obtain compound 5.59 (yield: 7%) as a pale white solid. LC-MS (LC-MS method P2): m / z 831.30 [M+H]+, 1.678 min.1 HNMR(400MHz,DMSO-d6)(FIDNO:ZJ-0523-038-HNMR)δ11.00(s,1H),8.27(t,J=5.8Hz,1H),8.13(t,J=5.8H z,1H),7.49-7.42(m,5H),7.34(d,J=7.6Hz,1H),7.12(d,J=8.2Hz,1H),5.13(d,J=8.4Hz,1H),4.64(s,2H), 4.52-4.42(m,3H),4.33(d,J=17.6Hz,2H),3.52(s,3H),3.45(q,J=3.2Hz,4H),3.27(d,J=10.8Hz,4H),2.97 -2.85(m,2H),2.59(s,3H),2.40(s,3H),1.99(d,J=7.0Hz,1H),1.61(s,2H),1.47(s,1H),1.28-1.23(m,3H)

[0253] Compound 5.60 was separated and purified by HPLC (5-50% ACN / 0.1% TFA containing water), and compound 5.60 (yield: 30%) was obtained as a white solid. LCMS: (LCMS method S12): m / z743.2[M+H] + 2.842 points 1 H NMR:(400MHz,DMSO-d6,FID No:LL-0450-145-HNMR)δ10.96(d,J=2.8Hz,1H),8.34(d,J=5.6Hz,1H),7.66-7.54(m,1H),7.52-7.43(m,3H),7.41(s,2H) ,7.34(dd,J=7.6,3.2Hz,1H),7.15(s,1H),5.10(s,1H),4.61(d,J=3.0Hz,2H),4.49(tt,J=9.6,4.8Hz,1H),4.45-4.38(m,1 H),4.32(dd,J=17.6,14.8Hz,1H),3.44(d,J=6.8Hz,1H),3.23(q,J=5.6Hz,5H),2.95-2.81(m,1H),2.59(d,J=11.8Hz,2H) ,2.44-2.35(m,3H),2.34-2.26(m,1H),1.95-1.87(m,1H),1.85-1.77(m,1H),1.57(d,J=15.2Hz,3H),1.06(t,J=6.8Hz,1H)

[0254] Example 9: Competition and Mobilization Activity The competitive and recruitment activities of the compounds described herein were measured according to the assays shown in Examples 1 and 2. IC50 or EC50 intensities are reported from strongest to weakest (i.e., +++ to +). "NA" indicates not applicable. [Table 10] [Table 11]

Claims

[Claim 1] General formula (A) ｋ -L １ or a compound having a salt, enantiomer, stereoisomer, polymorph, or N-oxide thereof. In the formula, A is a portion that binds to E3 ubiquitin ligase and has a structure selected from the group consisting of formulas I, II, III, IV, V, VI, VII, VIII, IX, and X; 【Chemistry 1】 L １ is a linker; Each A is allowed by the valence of L １ They are connected by covalent bonds; wherein R １ is aryl, -N(R ５ )-X-R ６ , -SO ２ R ５ , or -O(CH ２ ) ｍ R ５ , and any of these may be optionally substituted with one or more R ｗ groups permitted by valency; In the formula, R ２ is, aryl, -NH-(C ３ -C １０ ) heteroaryl, or -N(R ５ )-(CH ２ ) ｍ -X-(CH ２ ) ｎ -R ６ And each of these allows one or more R by valence. ｗ The base can be optionally replaced by; In the formula, R ３ is cyano, aryl, -NH-(C ３ -C １０ ) Heteroaryl, (C ３ -C １０ ) Heterocyclo, or -N(R ５ )-(CH ２ ) ｍ -X-(CH ２ ) ｎ -R ６ And each of these allows one or more R by valence. ｗ The base can be optionally replaced by; R ４ is halo, cyano, aryl, OR ５ , or -N(R ５ )-(CH ２ ) ｍ -X-(CH ２ ) ｎ -R ６ And each of these allows one or more R by valence. ｗ The base can be optionally replaced by; R ５ Each occurrence independently determines H and (C １ -C ３ ) alkyl, (C ３ -C １０ ) heterocyclo, (C ３ -C １０ ) Cycloalkyl, -(CH ２ ) ｎ - (C ３ -C １０ ) Cycloalkyl, -(CH ２ ) ｎ - (C ３ -C １０ ) Heterocyclo, - (CH ２ ) ｎ -Aryl, -(CH ２ ) ｎ - A heteroaryl, aryl, or heteroaryl, each of which contains one or more R atoms allowed by valence. ｗ The base can be optionally replaced by; R ６ Each occurrence independently of OH, (C １ -C ３ ) alkyl, -(C １ -C ３ ) Alkoxy, (C ３ -C １０ ) heterocyclo, (C ３ -C10) Cycloalkyl, -(CH ２ )n-(C ３ -C １０ ) Cycloalkyl, -(CH ２ )n-(C ３ -C １０ ) Heterocyclo, - (CH ２ )n-aryl, -(CH ２ ) n-heteroaryl, aryl, heteroaryl, or R ５ and R ６ These attach together with atoms, resulting in nitrogen-containing (C) ３ -C １０ ) form a heterocycle, and each of these contains one or more R atoms allowed by valence. ｗ The base can be optionally replaced by; R ７ is H, (C １ -C ３ ) alkyl, or R ７ and R ２６ together with the carbon to which they are bonded form a carbon-carbon double bond; R ８ , R ９ , R １０ , R １１ are each independently H, halo, OH, cyano, (C １ -C ３ )alkyl, (C １ -C ３ )alkoxy, aryl, or heteroaryl, any of which may be optionally substituted with one or more R ｗ groups permitted by valency; R １２ , R １３ , R １４ , R １５ These are H and NH, respectively, independently. ２ , (C １ -C ３ ) alkyl, -N(R ５ )-(CH ２ )m-N(R ５ )-X-R ６ And, however, R １２ , R １３ , R １４ , and R １５ Three or fewer substituents are H, and each of them contains one or more R atoms allowed by valence. ｗ It can be arbitrarily substituted in the base; R １６ NH ２ , or -N(R ５ )-(CH ２ ) ｍ -X-(CH ２ ) ｎ -R ６ And each of these allows one or more R by valence. ｗ The base can be optionally replaced by; R １７ is cyano, heteroaryl, -(CH ２ ) ｍ -C(O)OR ６ , or -N(R ５ )-(CH ２ ) ｍ -X-(CH ２ ) ｎ -R ６ And each of these allows one or more R by valence. ｗ The base can be optionally replaced by; R １８ , R １９ , R ２０ , R ２１ These are H, Halo, and (C) respectively, independently. １ -C ３ ) alkyl, (C １ -C ３ ) Alkoxy, or -N(R ５ )-X-R ６ And, however, R １８ , R １９ , R ２０ , R ２１ Two or fewer substituents among them are H; or R １８ , R １９ They, together with the carbon to which they are attached, (C ３ -C １０ ) Cycloalkyl or (C ３ -C １０ ) form a heterocycloid, or R １９ , R ２０ They, together with the carbon to which they are attached, (C ３ -C １０ ) Cycloalkyl or (C ３ -C １０ ) form a heterocycloid, or R ２０ , R ２１ They, together with the carbon to which they are attached, (C ３ -C １０ ) Cycloalkyl or (C ３ -C １０ ) form heterocycloids, and each of these is allowed by one or more R atoms depending on their valence. ｗ The base can be optionally replaced by; R ２５ is aryl, heteroaryl, or (C ３ -C １０ ) are heterocycloidal, and each of them has one or more R allowed by valence ｗ The base can be optionally replaced by; R ｗ Each instance independently consists of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkyl, while alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are halo, cyano, oxo (C ３ -C １０ ) heterocyclo, (C ３ -C １０ ) Cycloalkyl, -(CH ２ ) ｎ - (C ３ -C １０ ) Cycloalkyl, -(CH ２ ) ｎ - (C ３ -C １０ ) Heterocyclo, - (CH ２ ) ｎ -Aryl, -(CH ２ ) ｎ - It can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls; X is a bonding group, -SO ２ -, - (CH ２ ) ｎ C(O)(CH ２ ) ｍ -, -C(O)NH-, -C(O)N(R ｗ )-, -NHC(O)NH-, or -(CH ２ ) ｎ - and; Y １ -NHR ２５ ,-NHC(O)R ２５ , or -CHR ２５ R ２６ And; m is 0, 1, 2, 3, or 4; k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n is 0, 1, 2, 3, or 4.

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